JP2022115994A - Crisprに基づくゲノム修飾および制御 - Google Patents
Crisprに基づくゲノム修飾および制御 Download PDFInfo
- Publication number
- JP2022115994A JP2022115994A JP2022076698A JP2022076698A JP2022115994A JP 2022115994 A JP2022115994 A JP 2022115994A JP 2022076698 A JP2022076698 A JP 2022076698A JP 2022076698 A JP2022076698 A JP 2022076698A JP 2022115994 A JP2022115994 A JP 2022115994A
- Authority
- JP
- Japan
- Prior art keywords
- domain
- protein
- cell
- fusion protein
- rna
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 108091033409 CRISPR Proteins 0.000 title claims abstract description 106
- 230000004048 modification Effects 0.000 title abstract description 25
- 238000012986 modification Methods 0.000 title abstract description 25
- 230000033228 biological regulation Effects 0.000 title description 2
- 108020001507 fusion proteins Proteins 0.000 claims abstract description 186
- 102000037865 fusion proteins Human genes 0.000 claims abstract description 185
- 230000002759 chromosomal effect Effects 0.000 claims abstract description 182
- 108010042407 Endonucleases Proteins 0.000 claims abstract description 156
- 102000004533 Endonucleases Human genes 0.000 claims abstract description 156
- 238000000034 method Methods 0.000 claims abstract description 102
- 238000003776 cleavage reaction Methods 0.000 claims abstract description 100
- 230000007017 scission Effects 0.000 claims abstract description 100
- 125000003729 nucleotide group Chemical group 0.000 claims abstract description 98
- 239000002773 nucleotide Substances 0.000 claims abstract description 96
- 101710163270 Nuclease Proteins 0.000 claims abstract description 63
- 210000002257 embryonic structure Anatomy 0.000 claims abstract description 56
- 239000012636 effector Substances 0.000 claims abstract description 50
- 102100021579 Enhancer of filamentation 1 Human genes 0.000 claims abstract description 46
- 101000898310 Homo sapiens Enhancer of filamentation 1 Proteins 0.000 claims abstract description 46
- 230000014509 gene expression Effects 0.000 claims abstract description 40
- 108010077850 Nuclear Localization Signals Proteins 0.000 claims abstract description 24
- 210000003527 eukaryotic cell Anatomy 0.000 claims abstract description 21
- 239000012634 fragment Substances 0.000 claims abstract description 21
- 238000010354 CRISPR gene editing Methods 0.000 claims abstract 6
- 108091032973 (ribonucleotides)n+m Proteins 0.000 claims abstract 2
- 210000004027 cell Anatomy 0.000 claims description 182
- 108020005004 Guide RNA Proteins 0.000 claims description 148
- 108020004414 DNA Proteins 0.000 claims description 99
- 210000001161 mammalian embryo Anatomy 0.000 claims description 87
- 150000007523 nucleic acids Chemical class 0.000 claims description 77
- 241001465754 Metazoa Species 0.000 claims description 69
- 102000039446 nucleic acids Human genes 0.000 claims description 67
- 108020004707 nucleic acids Proteins 0.000 claims description 67
- 102000040430 polynucleotide Human genes 0.000 claims description 66
- 108091033319 polynucleotide Proteins 0.000 claims description 66
- 239000002157 polynucleotide Substances 0.000 claims description 66
- 230000005782 double-strand break Effects 0.000 claims description 40
- 230000000694 effects Effects 0.000 claims description 32
- 108010017070 Zinc Finger Nucleases Proteins 0.000 claims description 29
- 230000001105 regulatory effect Effects 0.000 claims description 28
- 239000013598 vector Substances 0.000 claims description 22
- 108020004999 messenger RNA Proteins 0.000 claims description 21
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 claims description 19
- 230000004049 epigenetic modification Effects 0.000 claims description 18
- 210000004962 mammalian cell Anatomy 0.000 claims description 18
- 230000008569 process Effects 0.000 claims description 17
- 102100025169 Max-binding protein MNT Human genes 0.000 claims description 15
- 239000000539 dimer Substances 0.000 claims description 15
- 239000003550 marker Substances 0.000 claims description 15
- 108091006107 transcriptional repressors Proteins 0.000 claims description 15
- 230000000295 complement effect Effects 0.000 claims description 12
- 210000005260 human cell Anatomy 0.000 claims description 11
- 108020004705 Codon Proteins 0.000 claims description 10
- 108010026638 endodeoxyribonuclease FokI Proteins 0.000 claims description 9
- 239000000833 heterodimer Substances 0.000 claims description 9
- 210000000130 stem cell Anatomy 0.000 claims description 9
- 241000251539 Vertebrata <Metazoa> Species 0.000 claims description 6
- 238000012258 culturing Methods 0.000 claims description 6
- 238000013519 translation Methods 0.000 claims description 6
- 230000033616 DNA repair Effects 0.000 claims description 5
- 241000206602 Eukaryota Species 0.000 claims description 5
- 101150038500 cas9 gene Proteins 0.000 claims description 3
- 108090000623 proteins and genes Proteins 0.000 description 128
- 102000004169 proteins and genes Human genes 0.000 description 93
- 235000018102 proteins Nutrition 0.000 description 89
- 230000008439 repair process Effects 0.000 description 33
- 238000011144 upstream manufacturing Methods 0.000 description 32
- 238000003780 insertion Methods 0.000 description 29
- 230000037431 insertion Effects 0.000 description 29
- 241000699666 Mus <mouse, genus> Species 0.000 description 26
- 239000013612 plasmid Substances 0.000 description 21
- 241000700159 Rattus Species 0.000 description 20
- 238000012217 deletion Methods 0.000 description 18
- 230000037430 deletion Effects 0.000 description 18
- 230000006780 non-homologous end joining Effects 0.000 description 17
- 108091028043 Nucleic acid sequence Proteins 0.000 description 16
- 238000000338 in vitro Methods 0.000 description 16
- 230000035772 mutation Effects 0.000 description 16
- 230000004568 DNA-binding Effects 0.000 description 14
- 108091026890 Coding region Proteins 0.000 description 13
- 230000001404 mediated effect Effects 0.000 description 13
- 238000001890 transfection Methods 0.000 description 13
- 238000006467 substitution reaction Methods 0.000 description 12
- 235000001014 amino acid Nutrition 0.000 description 11
- 239000013600 plasmid vector Substances 0.000 description 11
- 238000010453 CRISPR/Cas method Methods 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 10
- 230000014616 translation Effects 0.000 description 10
- 125000003275 alpha amino acid group Chemical group 0.000 description 9
- 229940024606 amino acid Drugs 0.000 description 9
- 108091092236 Chimeric RNA Proteins 0.000 description 8
- 150000001413 amino acids Chemical class 0.000 description 8
- 102000053602 DNA Human genes 0.000 description 7
- 108010008532 Deoxyribonuclease I Proteins 0.000 description 7
- 102000007260 Deoxyribonuclease I Human genes 0.000 description 7
- 101001000998 Homo sapiens Protein phosphatase 1 regulatory subunit 12C Proteins 0.000 description 7
- 102100035620 Protein phosphatase 1 regulatory subunit 12C Human genes 0.000 description 7
- 108091028113 Trans-activating crRNA Proteins 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 230000002068 genetic effect Effects 0.000 description 7
- 238000010362 genome editing Methods 0.000 description 7
- 239000000178 monomer Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 230000006798 recombination Effects 0.000 description 7
- 238000005215 recombination Methods 0.000 description 7
- 238000013518 transcription Methods 0.000 description 7
- 230000035897 transcription Effects 0.000 description 7
- 241000699800 Cricetinae Species 0.000 description 6
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 230000034431 double-strand break repair via homologous recombination Effects 0.000 description 6
- 108091006047 fluorescent proteins Proteins 0.000 description 6
- 102000034287 fluorescent proteins Human genes 0.000 description 6
- 238000003205 genotyping method Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 229910052725 zinc Inorganic materials 0.000 description 6
- 239000011701 zinc Substances 0.000 description 6
- 241000701022 Cytomegalovirus Species 0.000 description 5
- -1 EYFP Proteins 0.000 description 5
- 241000238631 Hexapoda Species 0.000 description 5
- 108090000246 Histone acetyltransferases Proteins 0.000 description 5
- 102000003893 Histone acetyltransferases Human genes 0.000 description 5
- 125000000539 amino acid group Chemical group 0.000 description 5
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 5
- 210000003734 kidney Anatomy 0.000 description 5
- 241000894007 species Species 0.000 description 5
- 238000010561 standard procedure Methods 0.000 description 5
- 241000283690 Bos taurus Species 0.000 description 4
- 108010051219 Cre recombinase Proteins 0.000 description 4
- 238000001712 DNA sequencing Methods 0.000 description 4
- 241000196324 Embryophyta Species 0.000 description 4
- 241000282326 Felis catus Species 0.000 description 4
- 108090000144 Human Proteins Proteins 0.000 description 4
- 102000003839 Human Proteins Human genes 0.000 description 4
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 208000009869 Neu-Laxova syndrome Diseases 0.000 description 4
- 241000288906 Primates Species 0.000 description 4
- 241000283984 Rodentia Species 0.000 description 4
- 238000010459 TALEN Methods 0.000 description 4
- 108010043645 Transcription Activator-Like Effector Nucleases Proteins 0.000 description 4
- 108091023040 Transcription factor Proteins 0.000 description 4
- 102000040945 Transcription factor Human genes 0.000 description 4
- 230000001464 adherent effect Effects 0.000 description 4
- 235000004279 alanine Nutrition 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 230000012361 double-strand break repair Effects 0.000 description 4
- 230000001939 inductive effect Effects 0.000 description 4
- 230000009437 off-target effect Effects 0.000 description 4
- 238000005457 optimization Methods 0.000 description 4
- 108010054624 red fluorescent protein Proteins 0.000 description 4
- 230000002103 transcriptional effect Effects 0.000 description 4
- 239000013603 viral vector Substances 0.000 description 4
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 3
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 3
- 108010053770 Deoxyribonucleases Proteins 0.000 description 3
- 102000016911 Deoxyribonucleases Human genes 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 108010068250 Herpes Simplex Virus Protein Vmw65 Proteins 0.000 description 3
- 102100022846 Histone acetyltransferase KAT2B Human genes 0.000 description 3
- 102100022893 Histone acetyltransferase KAT5 Human genes 0.000 description 3
- 102100038885 Histone acetyltransferase p300 Human genes 0.000 description 3
- 101000882390 Homo sapiens Histone acetyltransferase p300 Proteins 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 241001494479 Pecora Species 0.000 description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 description 3
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 3
- 101710137500 T7 RNA polymerase Proteins 0.000 description 3
- 230000027455 binding Effects 0.000 description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 210000000349 chromosome Anatomy 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 238000006471 dimerization reaction Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 210000002950 fibroblast Anatomy 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000001638 lipofection Methods 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 230000011987 methylation Effects 0.000 description 3
- 238000007069 methylation reaction Methods 0.000 description 3
- 201000000050 myeloid neoplasm Diseases 0.000 description 3
- 230000000149 penetrating effect Effects 0.000 description 3
- 230000008488 polyadenylation Effects 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 230000010076 replication Effects 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 230000005030 transcription termination Effects 0.000 description 3
- 241000251468 Actinopterygii Species 0.000 description 2
- 241000272517 Anseriformes Species 0.000 description 2
- 241000271566 Aves Species 0.000 description 2
- 102100021975 CREB-binding protein Human genes 0.000 description 2
- 102000014914 Carrier Proteins Human genes 0.000 description 2
- 108010051109 Cell-Penetrating Peptides Proteins 0.000 description 2
- 102000020313 Cell-Penetrating Peptides Human genes 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- 101000709520 Chlamydia trachomatis serovar L2 (strain 434/Bu / ATCC VR-902B) Atypical response regulator protein ChxR Proteins 0.000 description 2
- 108091035707 Consensus sequence Proteins 0.000 description 2
- 238000007400 DNA extraction Methods 0.000 description 2
- 241000702421 Dependoparvovirus Species 0.000 description 2
- 102220518659 Enhancer of filamentation 1_D10A_mutation Human genes 0.000 description 2
- 241000283073 Equus caballus Species 0.000 description 2
- 108700024394 Exon Proteins 0.000 description 2
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 2
- 102000005720 Glutathione transferase Human genes 0.000 description 2
- 108010070675 Glutathione transferase Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
- 102100039869 Histone H2B type F-S Human genes 0.000 description 2
- 108010033040 Histones Proteins 0.000 description 2
- 101001035372 Homo sapiens Histone H2B type F-S Proteins 0.000 description 2
- 101001046967 Homo sapiens Histone acetyltransferase KAT2A Proteins 0.000 description 2
- 101001047006 Homo sapiens Histone acetyltransferase KAT2B Proteins 0.000 description 2
- 101001046996 Homo sapiens Histone acetyltransferase KAT5 Proteins 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 108060004795 Methyltransferase Proteins 0.000 description 2
- 108091093037 Peptide nucleic acid Proteins 0.000 description 2
- 102000011755 Phosphoglycerate Kinase Human genes 0.000 description 2
- 102000014450 RNA Polymerase III Human genes 0.000 description 2
- 108010078067 RNA Polymerase III Proteins 0.000 description 2
- 230000004570 RNA-binding Effects 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- 108010083644 Ribonucleases Proteins 0.000 description 2
- 102000006382 Ribonucleases Human genes 0.000 description 2
- 108091028664 Ribonucleotide Proteins 0.000 description 2
- 241000714474 Rous sarcoma virus Species 0.000 description 2
- 241000700584 Simplexvirus Species 0.000 description 2
- 241000282887 Suidae Species 0.000 description 2
- 241000282898 Sus scrofa Species 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- 101001099217 Thermotoga maritima (strain ATCC 43589 / DSM 3109 / JCM 10099 / NBRC 100826 / MSB8) Triosephosphate isomerase Proteins 0.000 description 2
- 102000002933 Thioredoxin Human genes 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 2
- 230000021736 acetylation Effects 0.000 description 2
- 238000006640 acetylation reaction Methods 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 210000004102 animal cell Anatomy 0.000 description 2
- 210000004436 artificial bacterial chromosome Anatomy 0.000 description 2
- 210000001106 artificial yeast chromosome Anatomy 0.000 description 2
- 229940009098 aspartate Drugs 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 108010006025 bovine growth hormone Proteins 0.000 description 2
- 102000021178 chitin binding proteins Human genes 0.000 description 2
- 108091011157 chitin binding proteins Proteins 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 239000005547 deoxyribonucleotide Substances 0.000 description 2
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 210000001671 embryonic stem cell Anatomy 0.000 description 2
- 210000003754 fetus Anatomy 0.000 description 2
- 108010021843 fluorescent protein 583 Proteins 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 239000000710 homodimer Substances 0.000 description 2
- 238000002744 homologous recombination Methods 0.000 description 2
- 230000006801 homologous recombination Effects 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- 238000002703 mutagenesis Methods 0.000 description 2
- 231100000350 mutagenesis Toxicity 0.000 description 2
- 210000003098 myoblast Anatomy 0.000 description 2
- 210000004940 nucleus Anatomy 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 230000001124 posttranscriptional effect Effects 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 239000013636 protein dimer Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000007894 restriction fragment length polymorphism technique Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 239000002336 ribonucleotide Substances 0.000 description 2
- 125000002652 ribonucleotide group Chemical group 0.000 description 2
- 229910052594 sapphire Inorganic materials 0.000 description 2
- 239000010980 sapphire Substances 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 230000005783 single-strand break Effects 0.000 description 2
- 238000002741 site-directed mutagenesis Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000010381 tandem affinity purification Methods 0.000 description 2
- 230000002123 temporal effect Effects 0.000 description 2
- 108060008226 thioredoxin Proteins 0.000 description 2
- 229940094937 thioredoxin Drugs 0.000 description 2
- 238000003151 transfection method Methods 0.000 description 2
- 239000012096 transfection reagent Substances 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 230000005945 translocation Effects 0.000 description 2
- 210000002444 unipotent stem cell Anatomy 0.000 description 2
- 108091005957 yellow fluorescent proteins Proteins 0.000 description 2
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 1
- YMHOBZXQZVXHBM-UHFFFAOYSA-N 2,5-dimethoxy-4-bromophenethylamine Chemical compound COC1=CC(CCN)=C(OC)C=C1Br YMHOBZXQZVXHBM-UHFFFAOYSA-N 0.000 description 1
- KQPKMEYBZUPZGK-UHFFFAOYSA-N 4-[(4-azido-2-nitroanilino)methyl]-5-(hydroxymethyl)-2-methylpyridin-3-ol Chemical compound CC1=NC=C(CO)C(CNC=2C(=CC(=CC=2)N=[N+]=[N-])[N+]([O-])=O)=C1O KQPKMEYBZUPZGK-UHFFFAOYSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- 241000007910 Acaryochloris marina Species 0.000 description 1
- 241001135190 Acetohalobium Species 0.000 description 1
- 241000266272 Acidithiobacillus Species 0.000 description 1
- 241000605222 Acidithiobacillus ferrooxidans Species 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 241000640374 Alicyclobacillus acidocaldarius Species 0.000 description 1
- 241001655243 Allochromatium Species 0.000 description 1
- 102100021954 Alpha-tubulin N-acetyltransferase 1 Human genes 0.000 description 1
- 241000147155 Ammonifex degensii Species 0.000 description 1
- 235000002198 Annona diversifolia Nutrition 0.000 description 1
- 241001495180 Arthrospira Species 0.000 description 1
- 241000620196 Arthrospira maxima Species 0.000 description 1
- 240000002900 Arthrospira platensis Species 0.000 description 1
- 235000016425 Arthrospira platensis Nutrition 0.000 description 1
- 241000282672 Ateles sp. Species 0.000 description 1
- 108091005950 Azurite Proteins 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000906059 Bacillus pseudomycoides Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 241000590572 Bia <butterfly> Species 0.000 description 1
- 241001453380 Burkholderia Species 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 108010040163 CREB-Binding Protein Proteins 0.000 description 1
- 101150069031 CSN2 gene Proteins 0.000 description 1
- 101100381481 Caenorhabditis elegans baz-2 gene Proteins 0.000 description 1
- 241000178334 Caldicellulosiruptor Species 0.000 description 1
- 102000000584 Calmodulin Human genes 0.000 description 1
- 108010041952 Calmodulin Proteins 0.000 description 1
- 241001496650 Candidatus Desulforudis Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 1
- 108091005944 Cerulean Proteins 0.000 description 1
- 241000862448 Chlorocebus Species 0.000 description 1
- 241000282552 Chlorocebus aethiops Species 0.000 description 1
- 241000579895 Chlorostilbon Species 0.000 description 1
- 108010077544 Chromatin Proteins 0.000 description 1
- 102100031668 Chromodomain Y-like protein Human genes 0.000 description 1
- 102100035371 Chymotrypsin-like elastase family member 1 Human genes 0.000 description 1
- 101710138848 Chymotrypsin-like elastase family member 1 Proteins 0.000 description 1
- 108091005960 Citrine Proteins 0.000 description 1
- 241000193163 Clostridioides difficile Species 0.000 description 1
- 241000193155 Clostridium botulinum Species 0.000 description 1
- 108091033380 Coding strand Proteins 0.000 description 1
- 108700010070 Codon Usage Proteins 0.000 description 1
- 241000907165 Coleofasciculus chthonoplastes Species 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 241000938605 Crocodylia Species 0.000 description 1
- 241000065716 Crocosphaera watsonii Species 0.000 description 1
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 1
- 241000238424 Crustacea Species 0.000 description 1
- 108091005943 CyPet Proteins 0.000 description 1
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 1
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 1
- 230000035131 DNA demethylation Effects 0.000 description 1
- 102100036912 Desmin Human genes 0.000 description 1
- 108010044052 Desmin Proteins 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 241000255925 Diptera Species 0.000 description 1
- 241000255601 Drosophila melanogaster Species 0.000 description 1
- 108091005941 EBFP Proteins 0.000 description 1
- 108091005947 EBFP2 Proteins 0.000 description 1
- 108091005942 ECFP Proteins 0.000 description 1
- 101710099240 Elastase-1 Proteins 0.000 description 1
- 102100035074 Elongator complex protein 3 Human genes 0.000 description 1
- 102100037241 Endoglin Human genes 0.000 description 1
- 108010036395 Endoglin Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000289659 Erinaceidae Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241000326311 Exiguobacterium sibiricum Species 0.000 description 1
- 108060002716 Exonuclease Proteins 0.000 description 1
- 102000016359 Fibronectins Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 108010001515 Galectin 4 Proteins 0.000 description 1
- 102100039556 Galectin-4 Human genes 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 241000699694 Gerbillinae Species 0.000 description 1
- 102100039289 Glial fibrillary acidic protein Human genes 0.000 description 1
- 101710193519 Glial fibrillary acidic protein Proteins 0.000 description 1
- KOSRFJWDECSPRO-WDSKDSINSA-N Glu-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(O)=O KOSRFJWDECSPRO-WDSKDSINSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 1
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 102000008157 Histone Demethylases Human genes 0.000 description 1
- 108010074870 Histone Demethylases Proteins 0.000 description 1
- 102000011787 Histone Methyltransferases Human genes 0.000 description 1
- 108010036115 Histone Methyltransferases Proteins 0.000 description 1
- 102100022901 Histone acetyltransferase KAT2A Human genes 0.000 description 1
- 101710083341 Histone acetyltransferase KAT2B Proteins 0.000 description 1
- 101710116149 Histone acetyltransferase KAT5 Proteins 0.000 description 1
- 102100033071 Histone acetyltransferase KAT6A Human genes 0.000 description 1
- 102100033070 Histone acetyltransferase KAT6B Human genes 0.000 description 1
- 102100033068 Histone acetyltransferase KAT7 Human genes 0.000 description 1
- 102100033069 Histone acetyltransferase KAT8 Human genes 0.000 description 1
- 102100021467 Histone acetyltransferase type B catalytic subunit Human genes 0.000 description 1
- 102000043851 Histone deacetylase domains Human genes 0.000 description 1
- 108700038236 Histone deacetylase domains Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000896987 Homo sapiens CREB-binding protein Proteins 0.000 description 1
- 101000721661 Homo sapiens Cellular tumor antigen p53 Proteins 0.000 description 1
- 101000777795 Homo sapiens Chromodomain Y-like protein Proteins 0.000 description 1
- 101000877382 Homo sapiens Elongator complex protein 3 Proteins 0.000 description 1
- 101000828609 Homo sapiens Flotillin-2 Proteins 0.000 description 1
- 101000944179 Homo sapiens Histone acetyltransferase KAT6A Proteins 0.000 description 1
- 101000944174 Homo sapiens Histone acetyltransferase KAT6B Proteins 0.000 description 1
- 101000944166 Homo sapiens Histone acetyltransferase KAT7 Proteins 0.000 description 1
- 101000944170 Homo sapiens Histone acetyltransferase KAT8 Proteins 0.000 description 1
- 101000898976 Homo sapiens Histone acetyltransferase type B catalytic subunit Proteins 0.000 description 1
- 101000608935 Homo sapiens Leukosialin Proteins 0.000 description 1
- 101000934372 Homo sapiens Macrosialin Proteins 0.000 description 1
- 101000946889 Homo sapiens Monocyte differentiation antigen CD14 Proteins 0.000 description 1
- 101001111984 Homo sapiens N-acylneuraminate-9-phosphatase Proteins 0.000 description 1
- 101000602926 Homo sapiens Nuclear receptor coactivator 1 Proteins 0.000 description 1
- 101000602930 Homo sapiens Nuclear receptor coactivator 2 Proteins 0.000 description 1
- 101000974356 Homo sapiens Nuclear receptor coactivator 3 Proteins 0.000 description 1
- 101000585728 Homo sapiens Protein O-GlcNAcase Proteins 0.000 description 1
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 1
- 101000821100 Homo sapiens Synapsin-1 Proteins 0.000 description 1
- 101000777789 Homo sapiens Testis-specific chromodomain protein Y 1 Proteins 0.000 description 1
- 101000777786 Homo sapiens Testis-specific chromodomain protein Y 2 Proteins 0.000 description 1
- 101000666382 Homo sapiens Transcription factor E2-alpha Proteins 0.000 description 1
- 101000801209 Homo sapiens Transducin-like enhancer protein 4 Proteins 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- 108010091358 Hypoxanthine Phosphoribosyltransferase Proteins 0.000 description 1
- 102100029098 Hypoxanthine-guanine phosphoribosyltransferase Human genes 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 229930010555 Inosine Natural products 0.000 description 1
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 1
- 102100025306 Integrin alpha-IIb Human genes 0.000 description 1
- 101710149643 Integrin alpha-IIb Proteins 0.000 description 1
- 102100037872 Intercellular adhesion molecule 2 Human genes 0.000 description 1
- 101710148794 Intercellular adhesion molecule 2 Proteins 0.000 description 1
- 108020004684 Internal Ribosome Entry Sites Proteins 0.000 description 1
- 108091092195 Intron Proteins 0.000 description 1
- 239000007760 Iscove's Modified Dulbecco's Medium Substances 0.000 description 1
- 241001430080 Ktedonobacter racemifer Species 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- 241000186673 Lactobacillus delbrueckii Species 0.000 description 1
- 241000186869 Lactobacillus salivarius Species 0.000 description 1
- 241000282838 Lama Species 0.000 description 1
- 241000288903 Lemuridae Species 0.000 description 1
- 102100039564 Leukosialin Human genes 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 241000282553 Macaca Species 0.000 description 1
- 102100025136 Macrosialin Human genes 0.000 description 1
- 101710175625 Maltose/maltodextrin-binding periplasmic protein Proteins 0.000 description 1
- 241000206589 Marinobacter Species 0.000 description 1
- 102000006890 Methyl-CpG-Binding Protein 2 Human genes 0.000 description 1
- 108010072388 Methyl-CpG-Binding Protein 2 Proteins 0.000 description 1
- 102000016397 Methyltransferase Human genes 0.000 description 1
- 108010059724 Micrococcal Nuclease Proteins 0.000 description 1
- 241000192710 Microcystis aeruginosa Species 0.000 description 1
- 102100035877 Monocyte differentiation antigen CD14 Human genes 0.000 description 1
- 241000713333 Mouse mammary tumor virus Species 0.000 description 1
- 108010086093 Mung Bean Nuclease Proteins 0.000 description 1
- 241000282339 Mustela Species 0.000 description 1
- 102000008300 Mutant Proteins Human genes 0.000 description 1
- 108010021466 Mutant Proteins Proteins 0.000 description 1
- 102100023906 N-acylneuraminate-9-phosphatase Human genes 0.000 description 1
- 241000167284 Natranaerobius Species 0.000 description 1
- 241000244206 Nematoda Species 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 101100083259 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pho-4 gene Proteins 0.000 description 1
- 241000919925 Nitrosococcus halophilus Species 0.000 description 1
- 241001515112 Nitrosococcus watsonii Species 0.000 description 1
- 241000203622 Nocardiopsis Species 0.000 description 1
- 241001223105 Nodularia spumigena Species 0.000 description 1
- 108020004485 Nonsense Codon Proteins 0.000 description 1
- 241000192656 Nostoc Species 0.000 description 1
- 102100037223 Nuclear receptor coactivator 1 Human genes 0.000 description 1
- 102100037226 Nuclear receptor coactivator 2 Human genes 0.000 description 1
- 102100022883 Nuclear receptor coactivator 3 Human genes 0.000 description 1
- 241000192497 Oscillatoria Species 0.000 description 1
- 238000010222 PCR analysis Methods 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 108010088535 Pep-1 peptide Proteins 0.000 description 1
- 102000002508 Peptide Elongation Factors Human genes 0.000 description 1
- 108010068204 Peptide Elongation Factors Proteins 0.000 description 1
- 241000983938 Petrotoga mobilis Species 0.000 description 1
- 241000286209 Phasianidae Species 0.000 description 1
- 241000235648 Pichia Species 0.000 description 1
- 241000512220 Polaromonas Species 0.000 description 1
- 241001599925 Polaromonas naphthalenivorans Species 0.000 description 1
- 229920002873 Polyethylenimine Polymers 0.000 description 1
- 102100030122 Protein O-GlcNAcase Human genes 0.000 description 1
- 101710149951 Protein Tat Proteins 0.000 description 1
- 241000590028 Pseudoalteromonas haloplanktis Species 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 101100372762 Rattus norvegicus Flt1 gene Proteins 0.000 description 1
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 1
- 108010091086 Recombinases Proteins 0.000 description 1
- 102000018120 Recombinases Human genes 0.000 description 1
- 241000235070 Saccharomyces Species 0.000 description 1
- 101001025539 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) Homothallic switching endonuclease Proteins 0.000 description 1
- 241000288961 Saguinus imperator Species 0.000 description 1
- 241000282695 Saimiri Species 0.000 description 1
- 241000235346 Schizosaccharomyces Species 0.000 description 1
- 108091061750 Signal recognition particle RNA Proteins 0.000 description 1
- 241000256251 Spodoptera frugiperda Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- 241001431998 Streptococcus pyogenes MGAS15252 Species 0.000 description 1
- 241000194020 Streptococcus thermophilus Species 0.000 description 1
- 241001518258 Streptomyces pristinaespiralis Species 0.000 description 1
- 241000187191 Streptomyces viridochromogenes Species 0.000 description 1
- 241000203587 Streptosporangium roseum Species 0.000 description 1
- 102100021905 Synapsin-1 Human genes 0.000 description 1
- 241000192707 Synechococcus Species 0.000 description 1
- 101710192266 Tegument protein VP22 Proteins 0.000 description 1
- 241000255588 Tephritidae Species 0.000 description 1
- 102100031664 Testis-specific chromodomain protein Y 1 Human genes 0.000 description 1
- 102100031666 Testis-specific chromodomain protein Y 2 Human genes 0.000 description 1
- 241000206213 Thermosipho africanus Species 0.000 description 1
- 102000005747 Transcription Factor RelA Human genes 0.000 description 1
- 108010031154 Transcription Factor RelA Proteins 0.000 description 1
- 102100038313 Transcription factor E2-alpha Human genes 0.000 description 1
- 108050004072 Transcription initiation factor TFIID subunit 1 Proteins 0.000 description 1
- 102100035222 Transcription initiation factor TFIID subunit 1 Human genes 0.000 description 1
- 102100033763 Transducin-like enhancer protein 4 Human genes 0.000 description 1
- 241000078013 Trichormus variabilis Species 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 102000044159 Ubiquitin Human genes 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- 241000545067 Venus Species 0.000 description 1
- 241001416177 Vicugna pacos Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000003491 array Methods 0.000 description 1
- 229940011019 arthrospira platensis Drugs 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N biotin Natural products N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 108091005948 blue fluorescent proteins Proteins 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 229920006317 cationic polymer Polymers 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 230000004700 cellular uptake Effects 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 210000003483 chromatin Anatomy 0.000 description 1
- 239000011035 citrine Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 101150055601 cops2 gene Proteins 0.000 description 1
- 230000001351 cycling effect Effects 0.000 description 1
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 1
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical group NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 239000000412 dendrimer Substances 0.000 description 1
- 229920000736 dendritic polymer Polymers 0.000 description 1
- 210000005045 desmin Anatomy 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000005546 dideoxynucleotide Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 239000010976 emerald Substances 0.000 description 1
- 229910052876 emerald Inorganic materials 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 108010048367 enhanced green fluorescent protein Proteins 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 102000013165 exonuclease Human genes 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 230000004720 fertilization Effects 0.000 description 1
- 210000000604 fetal stem cell Anatomy 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 210000005046 glial fibrillary acidic protein Anatomy 0.000 description 1
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 238000005734 heterodimerization reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 238000000530 impalefection Methods 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 210000004263 induced pluripotent stem cell Anatomy 0.000 description 1
- 229960003786 inosine Drugs 0.000 description 1
- 239000012212 insulator Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 238000011670 long-evans rat Methods 0.000 description 1
- 210000005265 lung cell Anatomy 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 108091005949 mKalama1 Proteins 0.000 description 1
- 241001515942 marmosets Species 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 108091005573 modified proteins Proteins 0.000 description 1
- 102000035118 modified proteins Human genes 0.000 description 1
- 239000003147 molecular marker Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 210000002894 multi-fate stem cell Anatomy 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000037434 nonsense mutation Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000030648 nucleus localization Effects 0.000 description 1
- 230000009438 off-target cleavage Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 210000001778 pluripotent stem cell Anatomy 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 108010011110 polyarginine Proteins 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 108020001580 protein domains Proteins 0.000 description 1
- 230000019639 protein methylation Effects 0.000 description 1
- 230000004850 protein–protein interaction Effects 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 230000014493 regulation of gene expression Effects 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 102000037983 regulatory factors Human genes 0.000 description 1
- 108091008025 regulatory factors Proteins 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000001082 somatic cell Anatomy 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical group [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 108091008023 transcriptional regulators Proteins 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- GWBUNZLLLLDXMD-UHFFFAOYSA-H tricopper;dicarbonate;dihydroxide Chemical compound [OH-].[OH-].[Cu+2].[Cu+2].[Cu+2].[O-]C([O-])=O.[O-]C([O-])=O GWBUNZLLLLDXMD-UHFFFAOYSA-H 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000000277 virosome Substances 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
- C12N15/90—Stable introduction of foreign DNA into chromosome
- C12N15/902—Stable introduction of foreign DNA into chromosome using homologous recombination
- C12N15/907—Stable introduction of foreign DNA into chromosome using homologous recombination in mammalian cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/463—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from amphibians
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
- C12N15/102—Mutagenizing nucleic acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/67—General methods for enhancing the expression
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/86—Viral vectors
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
- C12N9/22—Ribonucleases RNAses, DNAses
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/96—Stabilising an enzyme by forming an adduct or a composition; Forming enzyme conjugates
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y301/00—Hydrolases acting on ester bonds (3.1)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y301/00—Hydrolases acting on ester bonds (3.1)
- C12Y301/21—Endodeoxyribonucleases producing 5'-phosphomonoesters (3.1.21)
- C12Y301/21004—Type II site-specific deoxyribonuclease (3.1.21.4)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/09—Fusion polypeptide containing a localisation/targetting motif containing a nuclear localisation signal
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/10—Fusion polypeptide containing a localisation/targetting motif containing a tag for extracellular membrane crossing, e.g. TAT or VP22
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/80—Fusion polypeptide containing a DNA binding domain, e.g. Lacl or Tet-repressor
- C07K2319/81—Fusion polypeptide containing a DNA binding domain, e.g. Lacl or Tet-repressor containing a Zn-finger domain for DNA binding
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/20—Type of nucleic acid involving clustered regularly interspaced short palindromic repeats [CRISPRs]
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/35—Nature of the modification
- C12N2310/351—Conjugate
- C12N2310/3513—Protein; Peptide
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
- C12N2750/00011—Details
- C12N2750/14011—Parvoviridae
- C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
- C12N2750/14141—Use of virus, viral particle or viral elements as a vector
- C12N2750/14143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2800/00—Nucleic acids vectors
- C12N2800/22—Vectors comprising a coding region that has been codon optimised for expression in a respective host
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2800/00—Nucleic acids vectors
- C12N2800/80—Vectors containing sites for inducing double-stranded breaks, e.g. meganuclease restriction sites
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Genetics & Genomics (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- General Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- Biophysics (AREA)
- Plant Pathology (AREA)
- Physics & Mathematics (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Virology (AREA)
- Immunology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Mycology (AREA)
- Cell Biology (AREA)
- Epidemiology (AREA)
- Toxicology (AREA)
- Gastroenterology & Hepatology (AREA)
- Ophthalmology & Optometry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Enzymes And Modification Thereof (AREA)
- Peptides Or Proteins (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
Description
本発明は、標的ゲノム修飾に関する。特に、本発明は、RNA誘導型エンドヌクレアーゼまたはCRISPR/Cas様タンパク質を含む融合タンパク質、および標的染色体配列を修飾または調節するための該タンパク質の使用方法に関する。
標的ゲノム修飾は、真核細胞、胚、および動物の遺伝子操作のための強力なツールである。例えば、外来性配列は、標的ゲノム部位に組み込まれ、および/または特定の内在性染色体配列は、欠失、不活性化または修飾され得る。現在の方法は、例えば、ジンクフィンガーヌクレアーゼ(ZFN)または転写アクティベーター様エフェクターヌクレアーゼ(TALEN)のような改変ヌクレアーゼの使用に依存している。これらのキメラヌクレアーゼは、非特異的DNA切断ドメインに連結したプログラム可能な配列特異的DNA結合分子を含む。しかしながら、それぞれの新規ゲノム標的は、新規の配列特異的DNA結合分子を含む新規ZFNまたはTALENの設計を必要とする。従って、これらのカスタム設計されたヌクレアーゼは、割高な費用が掛かり、製造に時間を要する傾向がある。さらに、ZFNおよびTALENの特異性は、それらがオフターゲット(off-target)の切断を仲介し得る程度のものである。
本開示の種々の面には、単離されたRNA誘導型エンドヌクレアーゼの提供であって、該エンドヌクレアーゼが、少なくとも1つの核局在化シグナル、少なくとも1つのヌクレアーゼドメイン、および切断のために特定のヌクレオチド配列にエンドヌクレアーゼを標的化するガイドRNAと相互作用する少なくとも1つのドメインを含む、エンドヌクレアーゼの提供が含まれる。一態様において、エンドヌクレアーゼは、Cas9タンパク質に由来し得る。別の態様において、エンドヌクレアーゼは、少なくとも1つの機能的ヌクレアーゼドメインを欠失するように修飾され得る。他の態様において、エンドヌクレアーゼは、細胞透過性ドメイン、マーカードメイン、または両方をさらに含み得る。別の態様において、エンドヌクレアーゼは、ガイドRNAを含むタンパク質-RNA複合体の一部であり得る。いくつかの例において、ガイドRNAは、標的部位に相補的な5’領域を含む単一分子であり得る。また、本明細書に記載のRNA誘導型エンドヌクレアーゼの何れかをコードする単離された核酸も提供する。いくつかの態様において、核酸は、例えばヒト細胞のような哺乳動物細胞における翻訳に最適化されているコドンであり得る。他の態様において、RNA誘導型エンドヌクレアーゼをコードする核酸配列は、プロモーター調節配列に操作可能に連結されていてよく、要すれば、ベクターの一部であってよい。他の態様において、プロモーター調節配列に操作可能に連結されていてよいRNA誘導型エンドヌクレアーゼをコードする配列を含むベクターはまた、プロモーター調節配列に操作可能に連結されていてよいガイドRNAをコードする配列も含み得る。
本発明は、少なくとも1つの核局在化シグナル、少なくとも1つのヌクレアーゼドメイン、および切断のためにエンドヌクレアーゼを特定のヌクレオチド配列に標的化するガイドRNAと相互作用する少なくとも1つのドメインを含む、RNA誘導型エンドヌクレアーゼを提供する。また、RNA誘導型エンドヌクレアーゼをコードする核酸、ならびに真核細胞または胚の染色体配列を修飾するための該RNA誘導型エンドヌクレアーゼの使用方法を提供する。RNA誘導型エンドヌクレアーゼは、それぞれがエンドヌクレアーゼを特定の標的部位に誘導し、その部位で、RNA誘導型エンドヌクレアーゼが、染色体配列が修飾されるようにDNA修復過程により修復され得る二本鎖の切断を導入する、複数の特定のガイドRNAと相互作用する。特異性がガイドRNAにより提供されるため、RNAベースのエンドヌクレアーゼが汎用され、異なるガイドRNAを用いて異なるゲノム配列を標的とするために使用され得る。本明細書に記載の方法は、特定の染色体配列を標的とし、修飾するため、および/または細胞または胚のゲノムにおける標的領域に内在性配列を導入するために使用され得る。さらに、標的化は、特異的であり、オフターゲット作用は制限されている。
本明細書に記載の一面は、真核細胞および胚、例えば、非ヒト単一細胞胚などの核へのエンドヌクレアーゼの移入を可能にする、少なくとも1つの核局在化シグナルを含むRNA誘導型エンドヌクレアーゼを提供する。RNA誘導型エンドヌクレアーゼはまた、少なくとも1つのヌクレアーゼドメインおよびガイドRNAと相互作用する少なくとも1つのドメインを含む。RNA誘導型エンドヌクレアーゼは、ガイドRNAによって特定の核酸配列(または標的部位)に誘導される。ガイドRNAは、一旦標的部位に誘導されると、RNA誘導型エンドヌクレアーゼが標的部位の核酸配列に二本鎖の切断を導入し得るように、RNA誘導型エンドヌクレアーゼならびに標的部位を相互作用させる。ガイドRNAは標的化切断のための特異性を提供するため、RNA誘導型エンドヌクレアーゼのエンドヌクレアーゼは汎用性であり、異なる標的核酸配列を切断するために異なるガイドRNAと共に用いることができる。本発明は、単離されたRNA誘導型エンドヌクレアーゼ、RNA誘導型エンドヌクレアーゼをコードする単離された核酸(すなわち、RNAまたはDNA)、RNA誘導型エンドヌクレアーゼをコードする核酸を含むベクター、およびRNA誘導型エンドヌクレアーゼ+ガイドRNAを含むタンパク質-RNA複合体を提供する。
本開示の別の面は、CRISPR/Cas様タンパク質またはそのフラグメントおよびエフェクタードメインを含む融合タンパク質を提供する。CRISPR/Cas様タンパク質は、ガイドRNAによって標的部位へ誘導され、その部位で、エフェクタードメインは、標的化核酸配列を修飾するか、またはそれに作用し得る。エフェクタードメインは、切断ドメイン、後成的修飾ドメイン、転写活性化ドメイン、または転写リプレッサードメインであり得る。融合タンパク質は、核局在化シグナル、細胞透過性ドメイン、またはマーカードメインから選択される少なくとも1つのさらなるドメインをさらに含み得る。
融合タンパク質は、CRISPR/Cas様タンパク質またはそのフラグメントを含む。CRISPR/Cas様タンパク質は、上記のセクション(I)に詳述している。CRISPR/Cas様タンパク質は、N末端、C末端、または融合タンパク質の内部に位置していてよい。
融合タンパク質は、エフェクタードメインもまた含む。エフェクタードメインは、切断ドメイン、後成的修飾ドメイン、転写活性化ドメイン、または転写リプレッサードメインであり得る。エフェクタードメインは、N末端、C末端、または融合タンパク質の内部に位置していてよい。
ある態様において、エフェクタードメインは切断ドメインである。本明細書で用いられている“切断ドメイン”は、DNAを切断するドメインを意味する。切断ドメインは、エンドヌクレアーゼまたはエキソヌクレアーゼから得られ得る。切断ドメインが由来し得るエンドヌクレアーゼの非限定的例には、制限エンドヌクレアーゼおよびホーミングエンドヌクレアーゼが含まれるが、これに限定されない。例えば、New England Biolabs Catalog or Belfort et al. (1997) Nucleic Acids Res. 25:3379-3388を参照のこと。DNAを切断するさらなる酵素が公知である(例えば、S1ヌクレアーゼ;マングビーンヌクレアーゼ;膵臓由来のDNase I;ミクロコッカルヌクレアーゼ;酵母のHO エンドヌクレアーゼ)。また、Linn et al. (eds.) Nucleases, Cold Spring Harbor Laboratory Press, 1993を参照のこと。これらの酵素(またはその機能的フラグメント)の1つまたはそれ以上は、切断ドメインの供給源として使用可能である。
他の態様において、融合タンパク質のエフェクタードメインは、後成的修飾ドメインであってよい。一般的に、後成的修飾ドメインは、DNA配列を改変することなく、ヒストン構造および/または染色体構造を変化させる。変化したヒストンおよび/またはクロマチン構造は、遺伝子発現の変化をもたらすことができる。後成的修飾の例には、ヒストンタンパク質中のリシン残基のアセチル化またはメチル化、およびDNA中のシトシン残基のメチル化が含まれるが、これらに限定されない。好適な後成的修飾ドメインの非限定的な例には、ヒストンアセチルトランスフェラーゼドメイン、ヒストン脱アセチル化酵素ドメイン、ヒストンメチルトランスフェラーゼドメイン、ヒストン脱メチル化酵素ドメイン、DNAメチルトランスフェラーゼドメイン、およびDNA脱メチル化酵素ドメインが含まれる。
他の態様において、融合タンパク質のエフェクタードメインは転写活性化ドメインであってよい。一般的に、転写活性化ドメインは、転写調節因子および/または転写調節タンパク質(すなわち、転写因子、RNAポリメラーゼなど)と相互作用して、遺伝子の転写を増加および/または活性化する。ある態様において、転写活性化ドメインは、ヘルペス単純ウイルス VP16 活性化ドメイン、VP64(VP16の四量体誘導体である)、NFκB p65 活性化ドメイン、p53 活性化ドメイン1および2、CREB(cAMP応答因子結合タンパク質)活性化ドメイン、E2A活性化ドメイン、およびNFAT(活性化T細胞の核因子)活性化ドメインであり得るが、これに限定されない。他の態様において、転写活性化ドメインは、Gal4、Gcn4、MLL、Rtg3、Gln3、Oaf1、Pip2、Pdr1、Pdr3、Pho4、およびLeu3であり得る。転写活性化ドメインは野生型であってよく、または、オリジナルの転写活性化ドメインの改変体であってもよい。ある態様において、融合タンパク質のエフェクタードメインは、VP16またはVP64転写活性化ドメインである。
さらに他の態様において、融合タンパク質のエフェクタードメインは、転写リプレッサードメインであってよい。一般的に、転写リプレッサードメインは、転写調節因子および/または転写調節タンパク質(すなわち、転写因子、RNAポリメラーゼなど)に相互作用して、遺伝子の転写を減少および/または終了させる。好適な転写リプレッサードメインの非限定的な例には、cAMP誘導性初期リプレッサー(ICER)ドメイン、Kruppel付随ボックスA(KRAB-A)リプレッサードメイン、YY1 グリシン富化リプレッサードメイン、Sp1様リプレッサー、E(spl)リプレッサー、IκBリプレッサー、およびMeCP2が含まれる。
ある態様において、融合タンパク質は、少なくとも1つのさらなるドメインをさらに含む。好適なさらなるドメインの非限定的な例には、核局在化シグナル、細胞透過性ドメインまたは転移ドメイン、およびマーカードメインが含まれる。好適な核局在化シグナル、細胞透過性ドメイン、およびマーカードメインの非限定的な例は、上記のセクション(I)に記載されている。
融合タンパク質のエフェクタードメインが切断ドメインである態様において、少なくとも1つの融合タンパク質を含む二量体を形成可能である。該二量体は、ホモ二量体またはヘテロ二量体であり得る。ある態様において、ヘテロ二量体は、2つの異なる融合タンパク質を含む。他の態様において、ヘテロ二量体は、1つの融合タンパク質とさらなるタンパク質を含む。
本開示の別の面は、上記セクション(I)および(II)にそれぞれ詳述したRNA誘導型エンドヌクレアーゼまたは融合タンパク質の何れかをコードする核酸を提供する。該核酸は、RNAまたはDNAであり得る。一態様において、RNA誘導型エンドヌクレアーゼまたは融合タンパク質をコードする核酸は、mRNAである。mRNAは、5’キャップ付加および/または3’ポリアデニル化されていてよい。別の態様において、RNA誘導型エンドヌクレアーゼまたは融合タンパク質をコードする核酸はDNAである。DNAはベクター中に存在していてよい(下記参照)。
本開示の別の面は、真核細胞または胚において染色体配列を修飾するための方法を包含する。該方法は、真核細胞または胚に、(i)少なくとも1つの核局在化シグナルを含む少なくとも1つのRNA誘導型エンドヌクレアーゼまたは少なくとも1つの核局在化シグナルを含む少なくとも1つのRNA誘導型エンドヌクレアーゼをコードする核酸、(ii)少なくとも1つのガイドRNAまたは少なくとも1つのガイドRNAをコードするDNA、および、要すれば(iii)ドナー配列を含む少なくとも1つのドナーポリヌクレオチドを導入することを含む。該方法は、各ガイドRNAが、染色体配列中の標的部位にRNA誘導型エンドヌクレアーゼを誘導し、そこでRNA誘導型エンドヌクレアーゼが、標的部位における二本鎖の切断を誘導し、二本鎖の切断が、染色体配列が修飾されるようにDNA修復過程により修復されるように、細胞または胚を培養することをさらに含む。
本方法は、細胞または胚に、少なくとも1つの核局在化シグナルを含む少なくとも1つのRNA誘導型エンドヌクレアーゼまたは少なくとも1つの核局在化シグナルを含む少なくとも1つのRNA誘導型エンドヌクレアーゼをコードする核酸を導入することを含む。かかるRNA誘導型エンドヌクレアーゼおよびRNA誘導型エンドヌクレアーゼをコードする核酸は、上記のセクション(I)および(III)にそれぞれ記載されている。
本方法はまた、細胞または胚に、少なくとも1つのガイドRNAまたは少なくとも1つのガイドRNAをコードするDNAを導入することも含む。ガイドRNAは、RNA誘導型エンドヌクレアーゼと相互作用して、エンドヌクレアーゼを、染色体配列中の特定のプロトスペーサー配列を有するガイドRNA塩基対の5’末端である特定の標的部位へ導く。
ガイドRNAと結合させたRNA誘導型エンドヌクレアーゼは、染色体配列中の標的部位に導かれ、そこで、RNA誘導型エンドヌクレアーゼは、染色体配列中に二本鎖の切断を導入する。標的部位は、配列がコンセンサス配列の直前(上流)に位置することを除いて、配列に何らの制限もない。このコンセンサス配列は、プロトスペーサー近接モチーフ(PAM)としても知られている。PAMの例には、NGG、NGGNG、およびNNAGAAW(ここで、Nは何れかのヌクレオチドを意味し、WはAまたはTを意味する)が含まれるが、これに限定されない。上記のセクション(IV)(b)に詳述の通り、ガイドRNAの第一の領域(5’末端)は、標的配列のプロトスペーサーに相補的である。典型的に、ガイドRNAの第一の領域は、約19から21ヌクレオチド長である。従って、ある面において、染色体配列中の標的部位の配列は、5’-N19-21-NGG-3’である。PAMは、イタリック体(NGG)である。
ある態様において、本方法は、胚内に少なくとも1つのドナーポリヌクレオチドを導入することをさらに含む。ドナーポリヌクレオチドは、少なくとも1つのドナー配列を含む。ある面において、ドナーポリヌクレオチドのドナー配列は、内在性または天然の染色体配列に相当する。例えば、ドナー配列は、標的部位で、またはその近位で染色体配列の一部と実質的に同一であり得るが、少なくとも1つのヌクレオチド変化を含む。従って、ドナー配列は、天然の配列への組み込みまたはその置換によって、標的染色***置での配列が少なくとも1つのヌクレオチド変更を含むように、標的部位で野生型配列の変形を含み得る。例えば、該変更は、1またはそれ以上のヌクレオチドの挿入、1またはそれ以上のヌクレオチドの欠失、1またはそれ以上のヌクレオチドの置換、またはそれらの組み合わせであり得る。修飾された配列の挿入の結果として、細胞または胚/動物は、標的の染色体配列から改変された遺伝子産物を生成し得る。
ある態様において、ドナーポリヌクレオチド中のドナー配列は、染色体配列中の標的部位の、それぞれ上流および下流に位置する配列と実質的に同一の配列を有する、上流配列および下流配列により挟まれている。これらの配列が類似であるため、ドナーポリヌクレオチドの上流および下流配列は、ドナー配列が染色体配列中に組み込まれ得る(または置換可能な)ように、ドナーポリヌクレオチドと標的染色体配列の相同組換えを可能にする。
他の態様において、ドナーポリヌクレオチドは、RNA誘導型エンドヌクレアーゼにより認識される少なくとも1つの標的切断部位をさらに含み得る。ドナーポリヌクレオチドに付加された標的切断部位は、ドナー配列の上流もしくは下流またはその上流および下流の両方に位置し得る。例えば、ドナー配列は、標的切断部位に隣接することが可能であり、すなわち、RNA誘導型エンドヌクレアーゼによる切断によって、該ドナー配列が、RNA誘導型エンドヌクレアーゼによる切断によって生じる染色体配列中のドナー配列と適合性のオーバーハングにより連結されている。従って、ドナー配列は、非相同的修復過程による二本鎖切断の修復中に切断された染色体配列と結合され得る。一般的に、標的切断部位(複数可)を含むドナーポリヌクレオチドは、環状であり得る(例えば、プラスミドベクターの一部であってよい)。
さらに別の態様において、ドナーポリヌクレオチドは、RNA誘導型エンドヌクレアーゼによって生じるオーバーハングと適合する任意の短いオーバーハングを有する短いドナー配列を含む直鎖状分子であり得る。かかる態様において、ドナー配列は、二本鎖の切断の修復中に切断された染色体配列と直接結合され得る。ある例において、ドナー配列は、約1,000未満、約500未満、約250未満、または約100ヌクレオチド未満であり得る。ある場合には、ドナーポリヌクレオチドは、平滑末端を有する短いドナー配列を含む直鎖状分子であり得る。他の例(iteration)において、ドナーポリヌクレオチドは、5’および/または3’オーバーハングを有する短いドナー配列を含む直鎖状分子であり得る。オーバーハングは、1、2、3、4または5ヌクレオチドを含んでいてよい。
RNA標的化エンドヌクレアーゼ(複数可)(またはそれをコード化する核酸)、ガイドRNA(複数可)(またはそれをコード化するDNA)、および任意のドナーポリヌクレオチド(複数可)は、種々の手段により細胞または胚に導入され得る。ある態様において、該細胞または胚は、トランスフェクトされる。好適なトランスフェクション法には、リン酸カルシウム仲介性トランスフェクション、ヌクレオフェクション(または、エレクトロポレーション)、陽イオン性ポリマーを用いるトランスフェクション(例えば、DEAE-デキストランまたはポリエチレンイミン)、ウイルス形質導入、ビロソーム(virosome)を用いるトランスフェクション、ビリオンを介するトランスフェクション、リポソームトランスフェクション、陽イオン性リポソームを用いるトランスフェクション、免疫リポソーム(immunoliposome)を用いるトランスフェクション、非リポソーム系脂質を用いるトランスフェクション、デンドリマートランスフェクション、熱ショックトランスフェクション、マグネトフェクション、リポフェクション、遺伝子銃送達、インペールフェクション、ソノポレーション、光学トランスフェクション、および特殊薬物存在下の核酸取り込みが含まれる。トランスフェクション法は、当技術分野で公知である(例えば、“Current Protocols in Molecular Biology” Ausubel et al., John Wiley & Sons, New York, 2003 または “Molecular Cloning: A Laboratory Manual” Sambrook & Russell、Cold Spring Harbor Press, Cold Spring Harbor, NY, 3rd edition, 2001を参照のこと)。他の態様において、分子は、マイクロインジェクションにより細胞または胚に導入される。典型的に、胚は、目的の種の受精後の1細胞期胚である。例えば、分子は、注入によって1細胞胚の前核に注入することができる。
本方法は、ガイドRNA(複数可)がRNA誘導型エンドヌクレアーゼ(複数可)を染色体配列中の標的部位(複数可)に導き、RNA誘導型エンドヌクレアーゼ(複数可)が染色体配列中に少なくとも1つの二本鎖の切断を導入するのに適当な条件下で、細胞または胚を維持することをさらに含む。二本鎖切断は、染色体配列が、少なくとも1つのヌクレオチドの欠失、少なくとも1つのヌクレオチドの挿入、少なくとも1つのヌクレオチドの置換、またはそれらの組み合わせにより修飾されるように、DNA修復過程により修復され得る。
広範囲の真核細胞および胚が、本方法における使用に好適である。例えば、細胞は、ヒト細胞、非ヒト哺乳動物細胞、非哺乳動物脊椎動物細胞、無脊椎動物細胞、昆虫細胞、植物細胞、酵母細胞、または単細胞真核生物であり得る。一般的に、胚は、非ヒト哺乳動物胚である。特定の態様において、胚は、1つの細胞の非ヒト哺乳動物胚であり得る。1つの細胞胚を含む哺乳動物胚の例には、マウス胚、ラット胚、ハムスター胚、げっ歯動物胚、ウサギ胚、ネコ胚、ヒツジ胚、ブタ胚、ウシ胚、ウマ胚、および霊長動物胚が含まれるが、これに限定されない。さらに他の態様において、細胞は幹細胞であり得る。好適な幹細胞には、胚性幹細胞、ES様幹細胞、胎生幹細胞、成体幹細胞、多能性幹細胞、誘導多能性幹細胞、多能性(multipotent)幹細胞、少能性(oligopotent)幹細胞、および単能性(unipotent)幹細胞等が含まれるが、これらに限定されない。例示的態様において、細胞は哺乳動物細胞である。
本開示の別の面は、細胞または胚において、染色体配列を修飾するか、または染色体配列の発現を制御するための方法を包含する。本方法は、細胞または胚へ、(a)少なくとも1つの融合タンパク質または少なくとも1つの融合タンパク質をコード化する核酸(ここで、該融合タンパク質は、CRISPR/Cas様タンパク質またはそのフラグメントおよびエフェクタードメインを含む)、および(b)少なくとも1つのガイドRNAまたはガイドRNAをコード化するDNA(ここで、該ガイドRNAは、融合タンパク質のCRISPR/Cas様タンパク質を染色体配列中の標的部位に誘導し、融合タンパク質のエフェクタードメインが染色体配列を修飾するか、または染色体配列の発現を制御する。)を導入することを含む。
本開示は、RNA誘導型エンドヌクレアーゼにより仲介されるか、または融合タンパク質により仲介される過程を用いて、例えば、本明細書に記載の方法を用いて修飾されている、少なくとも1つの染色体配列を含む遺伝子的に修飾された細胞、非ヒト胚および非ヒト動物を包含する。本開示は、目的の染色体配列または融合タンパク質、少なくとも1つのガイドRNA、および所望により、1つまたはそれ以上のドナーポリヌクレオチド(複数可)に対して標的化されたRNA誘導型エンドヌクレアーゼまたは融合タンパク質をコード化する少なくとも1つのDNAまたはRNA分子を含む細胞を提供する。本開示はまた、目的の染色体配列、少なくとも1つのガイドRNA、および所望により、1つまたはそれ以上のドナーポリヌクレオチド(複数可)に対して標的化されたRNA誘導型エンドヌクレアーゼまたは融合タンパク質をコード化する少なくとも1つのDNAまたはRNA分子を含む非ヒト胚を提供する。
特に他に定義されない限り、本明細書で用いる全ての技術用語および科学用語は、本発明の属する分野の当業者に通常理解される意味を有する。以下の参考文献は、本発明に使用される多くの用語の一般的定義を当業者に提供する:Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); および、 Hale & Marham, The Harper Collins Dictionary of Biology (1991)。本明細書で用いる通り、以下の用語は、他に特に記載されない限り、それらの有する普通の意味を有する。
以下の実施例は、本発明のある面を説明する。
ストレプトコッカス・ピオゲネス(Streptococcus pyogenes)株MGAS15252(受託番号YP_005388840.1)由来のCas9遺伝子を、哺乳動物細胞におけるその翻訳を強化するためにヒト(ホモ・サピエンス)のコドンで優先的に最適化した。Cas9遺伝子はまた、哺乳動物細胞の核に該タンパク質を標的化するためにC末端に核局在化シグナルPKKKRKV(配列番号1)を付加することにより修飾された。表1は、修飾されたCas9アミノ酸配列を示し、核局在化配列は下線で示される。表2は、コドンを最適化した修飾されたCas9 DNA配列を示す。
アデノ随伴ウイルス挿入部位1(AAVS1)遺伝子座を、Cas9仲介性ヒトゲノム修飾のための標的として用いた。ヒト AAVS1遺伝子座は、タンパク質ホスファターゼ1、調節サブユニット12C(PPP1R12C)のイントロン1(4427bp)に位置する。表3は、PPP1R12Cの第一エクソン(網掛け灰色部分)および第一イントロンを示す。イントロン内の下線を付した配列は、標的修飾部位(すなわち、AAVS1遺伝子座)である。
PPP1R12CのN末端へのGFPタンパク質の特異的挿入を、Cas9仲介性ゲノム修飾をモニターするために用いた。相同組換えによる挿入を仲介するために、ドナーポリヌクレオチドを調製した。AAVS1-GFP DNA ドナーは、5’(1185bp)のAAVS1遺伝子座の相同アーム、RNAスプライシング受容体、ターボGFPコーディング配列、3’転写ターミネーター、および3’(1217bp)のAAVS1遺伝子座の相同アームを含んでいた。表5は、RNAスプライシング受容体の配列および3’転写ターミネーターが続くGFPコーディング配列を示す。プラスミドDNAを、GenEluteエンドトキシンフリープラスミドMaxiprep Kit(Sigma)を用いて調製した。
トランスフェクションをヒトK562細胞で行った。K562細胞株をAmerican Type Culture Collection (ATCC)より入手し、10%FBSおよび2mMのL-グルタミンを添加したイスコフ改変ダルベッコ培地中で増殖させた。全ての培地および添加物は、Sigma-Aldrichより入手した。培養物をトランスフェクションの1日前に(1mL当たり約50万個の細胞で)分割した。細胞を、T-016プログラムを用いてNucleofector (Lonza)のNucleofector ソリューションV(Lonza)を用いてトランスフェクションした。各ヌクレオフェクション(nucleofection)溶液は、約60万個の細胞を含んだ。トランスフェクション処理を表7に詳述する。細胞を、ヌクレオフェクション直後に37℃および5% CO2で増殖させた。
ゲノムDNAを、トランスフェクションの12日後にGenElute Mammalian Genomic DNA Miniprep Kit (Sigma)を用いてトランスフェクション細胞から抽出した。その後、ゲノムDNAを、AAVS1-GFPプラスミドドナーの5’相同アームの外側に位置するフォワードプライマーおよびGFPの5’領域に位置するリバースプライマーを用いて、PCR増幅させた。フォワードプライマーは、5’-CCACTCTGTGCTGACCACTCT-3’(配列番号18)であり、リバースプライマーは、5’-GCGGCACTCGATCTCCA-3’(配列番号19)であった。ジャンクションPCRから予期されるフラグメントサイズは、1388bpであった。増幅を、以下のサイクル条件を用いてJumpStart Taq ReadyMix (Sigma)を用いて行った:最初の変性のために98℃で2分間;98℃で15秒間、62℃で30秒間、および72℃で1分30秒を35サイクル;そして、最後の伸張を72℃で5分間。PCR産物を1%アガロースゲル上で分離した。
マウスRosa26遺伝子座を、ゲノム編集のための標的とし得る。表8は、マウスRosa26配列の一部を示し、そこで、可能性のある標的部位を太字で示す。各標的部位は、プロトスペーサーを含む。
Rosa26遺伝子座は、上記のセクション(IV)(d)に詳述した通り、ドナーポリヌクレオチドを上記の実施例6に記載のプレアニーリングしたcrRNA/tracrRNAおよび修飾されたCas9タンパク質をコード化するmRNAと共にインジェクションすることによりマウス胚において修飾され得る。生産動物由来のインビトロでインキュベートされた胚または組織(実施例6に記載)を、PCRに基づく遺伝子型決定法、例えばRFLPアッセイ、ジャンクションPCR、およびDNA配列決定等を用いて修飾されたRosa26遺伝子座についてスクリーニングすることができる。
ラットRosa26遺伝子座を、ゲノム修飾の標的とすることができる。表10は、ラット配列の一部を示し、そこで、可能性のある標的部位は太字で示される。各標的部位はプロトスペーサーを含む。
Rosa26遺伝子座は、上記のセクション(IV)(d)に詳述した通り、ドナーポリヌクレオチドを上記の実施例8に記載のプレアニーリングしたcrRNA/tracrRNAおよび修飾されたCas9をコード化するmRNAと共にインジェクションすることによりラット胚において修飾され得る。生産ラット由来のインビトロでインキュベートされた胚または組織(実施例8に記載)を、PCRに基づく遺伝子型決定法、例えばRFLPアッセイ、ジャンクションPCR、およびDNA配列決定等を用いて修飾されたRosa26遺伝子座についてスクリーニングすることができる。
Claims (48)
- 少なくとも1つの核局在化シグナル、少なくとも1つのヌクレアーゼドメイン、および切断のために特定のヌクレオチド配列にエンドヌクレアーゼを標的化するためのガイドRNAと相互作用する少なくとも1つのドメインを含む、単離されたエンドヌクレアーゼ。
- 該エンドヌクレアーゼがCas9タンパク質に由来する、請求項1に記載の単離されたエンドヌクレアーゼ。
- エンドヌクレアーゼが、少なくとも1つの機能的ヌクレアーゼドメインを欠失するように修飾されている、請求項1または2に記載の単離されたエンドヌクレアーゼ。
- 細胞透過性ドメイン、マーカードメイン、または両方をさらに含む、請求項1から3のいずれか一項に記載の単離されたエンドヌクレアーゼ。
- ガイドRNAを含むタンパク質-RNA複合体の一部である、請求項1から4のいずれか一項に記載の単離されたエンドヌクレアーゼ。
- ガイドRNAが、標的部位に相補的である5’領域を含む単一分子である、請求項5に記載の単離されたエンドヌクレアーゼ。
- 請求項1から4のいずれか一項に記載のエンドヌクレアーゼをコードする単離された核酸。
- 核酸が、哺乳動物細胞における翻訳に最適なコドンである、請求項7に記載の単離された核酸。
- 核酸が、ヒト細胞における翻訳に最適なコドンである、請求項7に記載の単離された核酸。
- プロモーター調節配列に操作可能に連結されている、請求項7から9のいずれか一項に記載の単離された核酸。
- 請求項10に記載の単離された核酸を含むベクター。
- プロモーター調節配列に操作可能に連結されているガイドRNAをコードする配列をさらに含む、請求項11に記載のベクター。
- 真核細胞または胚において染色体配列を修飾するための方法であって、
a)真核細胞または胚に、(i)少なくとも1つの核局在化シグナルを含む少なくとも1つのRNA誘導型エンドヌクレアーゼ、または少なくとも1つの核局在化シグナルを含む少なくとも1つのRNA誘導型エンドヌクレアーゼをコードする核酸、(ii)少なくとも1つのガイドRNAまたは少なくとも1つのガイドRNAをコードするDNA、および任意に、(iii)少なくとも1つのドナーポリヌクレオチドを導入し、
b)真核細胞または胚を、各ガイドRNAが、RNA誘導型エンドヌクレアーゼを染色体配列中の標的部位へ誘導し、そこでRNA誘導型エンドヌクレアーゼが、該標的部位にて二本鎖の切断を誘導し、該二本鎖の切断が、染色体配列が修飾されるようにDNA修復過程により修復されるように培養することを含む、
方法。 - RNA誘導型エンドヌクレアーゼがCas9タンパク質に由来する、請求項13に記載の方法。
- RNA誘導型エンドヌクレアーゼをコードする核酸がmRNAである、請求項13または14に記載の方法。
- RNA誘導型エンドヌクレアーゼをコードする核酸がDNAである、請求項13または14に記載の方法。
- DNAが、ガイドRNAをコードする配列をさらに含むベクターの一部である、請求項16に記載の方法。
- 真核細胞が、ヒト細胞、非ヒト哺乳動物細胞、幹細胞、非哺乳動物脊椎動物細胞、無脊椎動物細胞、植物細胞、または単細胞真核生物である、請求項13から17のいずれか一項に記載の方法。
- 胚が、非ヒト単一細胞動物胚である、請求項13から17のいずれか一項に記載の方法。
- CRISPR/Cas様タンパク質またはそのフラグメントおよびエフェクタードメインを含む、融合タンパク質。
- CRISPR/Cas様タンパク質が、Cas9タンパク質に由来する、請求項20に記載の融合タンパク質。
- Cas9タンパク質が、少なくとも1つの機能的ヌクレアーゼドメインを欠失するように修飾されている、請求項21に記載の融合タンパク質。
- Cas9タンパク質が、全てのヌクレアーゼ活性を欠失するように修飾されている、請求項21に記載の融合タンパク質。
- エフェクタードメインが切断ドメインである、請求項20から23のいずれか一項に記載の融合タンパク質。
- 切断ドメインが、FokIエンドヌクレアーゼドメインまたは修飾FokI切断ドメインである、請求項24に記載の融合タンパク質。
- 融合タンパク質が、第二の融合タンパク質と二量体を形成する、請求項25に記載の融合タンパク質。
- 融合タンパク質が、FokIエンドヌクレアーゼドメインまたは修飾FokI切断ドメインを含むジンクフィンガーヌクレアーゼとヘテロ二量体を形成する、請求項25に記載の融合タンパク質。
- CRISPR/Cas様タンパク質が、全てのヌクレアーゼ活性を欠失するように修飾されたCas9タンパク質に由来し、エフェクタードメインが、FokIエンドヌクレアーゼドメインまたは修飾FokI切断ドメインである、請求項20に記載の融合タンパク質。
- エフェクタードメインが、転写活性化ドメイン、転写リプレッサードメイン、および後成的修飾ドメインから選択される、請求項20から23のいずれか一項に記載の融合タンパク質。
- 融合タンパク質が、核局在化シグナル、細胞透過性ドメイン、およびマーカードメインから選択される少なくとも1つのさらなるドメインをさらに含む、請求項20から29のいずれか一項に記載の融合タンパク質。
- 請求項20から30のいずれか一項に記載の融合タンパク質をコードする単離された核酸。
- 染色体配列を修飾する方法、または細胞もしくは胚における染色体配列の発現を調節する方法であって、該細胞または胚に、(a)少なくとも1つの融合タンパク質または少なくとも1つの融合タンパク質をコードする核酸(ここで、該融合タンパク質は、CRISPR/Cas様タンパク質またはそのフラグメントおよびエフェクタードメインを含む。)、および(b)少なくとも1つのガイドRNAまたは少なくとも1つのガイドRNAをコードするDNA(ここで、該1つのガイドRNAは、融合タンパク質のCRISPR/Cas様タンパク質を染色体配列の標的部位へ誘導し、融合タンパク質のエフェクタードメインは、該染色体配列を修飾するか、または該染色体配列の発現を制御する。)を導入することを含む、方法。
- CRISPR/Cas様タンパク質が、Cas9タンパク質に由来する、請求項32に記載の方法。
- cas9タンパク質が、少なくとも1つの機能的ヌクレアーゼドメインを欠失するように修飾される、請求項33に記載の方法。
- cas9タンパク質が、全てのヌクレアーゼ活性を欠失するように修飾される、請求項33に記載の方法。
- 融合タンパク質が、核局在化シグナル、細胞透過性ドメイン、およびマーカードメインから選択される少なくとも1つのさらなるドメインをさらに含む、請求項32から35のいずれか一項に記載の方法。
- エフェクタードメインが切断ドメインである、請求項32から36のいずれか一項に記載の方法。
- 1つの融合タンパク質または1つの融合タンパク質をコードする核酸および2つのガイドRNAまたは2つのガイドRNAをコードするDNAが、細胞または胚に導入される、請求項37に記載の方法。
- 融合タンパク質が、Cas9タンパク質またはそのフラグメントおよびFokI切断ドメインまたは修飾FokI切断ドメインを含む、請求項38に記載の方法。
- 2つの融合タンパク質または2つの融合タンパク質をコードする核酸および2つのガイドRNAまたは2つのガイドRNAをコードするDNAが、細胞または胚に導入される、請求項37に記載の方法。
- 各融合タンパク質が、異なるCas9タンパク質もしくはそのフラグメントおよび/またはFokI切断ドメインもしくは修飾FokI切断ドメインを含む、請求項40に記載の方法。
- 1つの融合タンパク質または1つの融合タンパク質をコードする核酸、1つのガイドRNAまたは1つのガイドRNAをコードするDNA、ならびに1つのジンクフィンガーヌクレアーゼまたは1つのジンクフィンガーヌクレアーゼをコードする核酸が、細胞または胚に導入される、請求項37に記載の方法。
- 融合タンパク質が、Cas9タンパク質またはそのフラグメントおよびFokI切断ドメインまたはその誘導体を含み、ジンクフィンガーヌクレアーゼが、FokI切断ドメインまたは修飾FokI切断ドメインを含む、請求項42に記載の方法。
- 細胞または胚に少なくとも1つのドナーポリヌクレオチドを導入することをさらに含む、請求項37から43のいずれか一項に記載の方法。
- エフェクタードメインが、後成的修飾ドメイン、転写活性化ドメイン、または転写リプレッサードメインから選択される、請求項32から36のいずれか一項に記載の方法。
- 1つの融合タンパク質または1つの融合タンパク質をコードする核酸、および1つのガイドRNAまたは1つのガイドRNAをコードするDNAが、細胞または胚に導入される、請求項45に記載の方法。
- 細胞が、ヒト細胞、非ヒト哺乳動物細胞、幹細胞、非哺乳動物脊椎動物細胞、無脊椎動物細胞、植物細胞、または単細胞真核生物である、請求項32から46のいずれか一項に記載の方法。
- 胚が非ヒト単一細胞動物胚である、請求項32から46のいずれか一項に記載の方法。
Applications Claiming Priority (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201261734256P | 2012-12-06 | 2012-12-06 | |
US61/734,256 | 2012-12-06 | ||
US201361758624P | 2013-01-30 | 2013-01-30 | |
US61/758,624 | 2013-01-30 | ||
US201361761046P | 2013-02-05 | 2013-02-05 | |
US61/761,046 | 2013-02-05 | ||
US201361794422P | 2013-03-15 | 2013-03-15 | |
US61/794,422 | 2013-03-15 | ||
JP2020074283A JP2020120674A (ja) | 2012-12-06 | 2020-04-17 | Crisprに基づくゲノム修飾および制御 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020074283A Division JP2020120674A (ja) | 2012-12-06 | 2020-04-17 | Crisprに基づくゲノム修飾および制御 |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2022115994A true JP2022115994A (ja) | 2022-08-09 |
JP2022115994A5 JP2022115994A5 (ja) | 2022-10-06 |
JP7478772B2 JP7478772B2 (ja) | 2024-05-07 |
Family
ID=50883989
Family Applications (6)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2015545838A Active JP6620018B2 (ja) | 2012-12-06 | 2013-12-05 | Crisprに基づくゲノム修飾および制御 |
JP2017115672A Pending JP2017192392A (ja) | 2012-12-06 | 2017-06-13 | Crisprに基づくゲノム修飾および制御 |
JP2018183815A Pending JP2019037231A (ja) | 2012-12-06 | 2018-09-28 | Crisprに基づくゲノム修飾および制御 |
JP2020074283A Pending JP2020120674A (ja) | 2012-12-06 | 2020-04-17 | Crisprに基づくゲノム修飾および制御 |
JP2021033258A Pending JP2021101706A (ja) | 2012-12-06 | 2021-03-03 | Crisprに基づくゲノム修飾および制御 |
JP2022076698A Active JP7478772B2 (ja) | 2012-12-06 | 2022-05-06 | Crisprに基づくゲノム修飾および制御 |
Family Applications Before (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2015545838A Active JP6620018B2 (ja) | 2012-12-06 | 2013-12-05 | Crisprに基づくゲノム修飾および制御 |
JP2017115672A Pending JP2017192392A (ja) | 2012-12-06 | 2017-06-13 | Crisprに基づくゲノム修飾および制御 |
JP2018183815A Pending JP2019037231A (ja) | 2012-12-06 | 2018-09-28 | Crisprに基づくゲノム修飾および制御 |
JP2020074283A Pending JP2020120674A (ja) | 2012-12-06 | 2020-04-17 | Crisprに基づくゲノム修飾および制御 |
JP2021033258A Pending JP2021101706A (ja) | 2012-12-06 | 2021-03-03 | Crisprに基づくゲノム修飾および制御 |
Country Status (17)
Country | Link |
---|---|
US (15) | US20160017366A1 (ja) |
EP (11) | EP3617309A3 (ja) |
JP (6) | JP6620018B2 (ja) |
KR (6) | KR101844123B1 (ja) |
CN (3) | CN108715602A (ja) |
AU (9) | AU2013355214B2 (ja) |
BR (1) | BR112015012375A2 (ja) |
CA (3) | CA2977152C (ja) |
DK (6) | DK3363902T3 (ja) |
ES (6) | ES2713243T3 (ja) |
HK (1) | HK1218389A1 (ja) |
IL (5) | IL300199A (ja) |
LT (4) | LT3138912T (ja) |
PL (6) | PL2928496T3 (ja) |
PT (6) | PT3138912T (ja) |
SG (4) | SG10201800585VA (ja) |
WO (1) | WO2014089290A1 (ja) |
Families Citing this family (365)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008027558A2 (en) | 2006-08-31 | 2008-03-06 | Codon Devices, Inc. | Iterative nucleic acid assembly using activation of vector-encoded traits |
EP2638157B1 (en) | 2010-11-12 | 2015-07-22 | Gen9, Inc. | Methods and devices for nucleic acids synthesis |
EP4039363A1 (en) | 2010-11-12 | 2022-08-10 | Gen9, Inc. | Protein arrays and methods of using and making the same |
EP3613852A3 (en) | 2011-07-22 | 2020-04-22 | President and Fellows of Harvard College | Evaluation and improvement of nuclease cleavage specificity |
EP3594340B1 (en) | 2011-08-26 | 2021-06-30 | Gen9, Inc. | Compositions and methods for high fidelity assembly of nucleic acids |
US11021737B2 (en) | 2011-12-22 | 2021-06-01 | President And Fellows Of Harvard College | Compositions and methods for analyte detection |
GB201122458D0 (en) | 2011-12-30 | 2012-02-08 | Univ Wageningen | Modified cascade ribonucleoproteins and uses thereof |
US9637739B2 (en) | 2012-03-20 | 2017-05-02 | Vilnius University | RNA-directed DNA cleavage by the Cas9-crRNA complex |
US9150853B2 (en) | 2012-03-21 | 2015-10-06 | Gen9, Inc. | Methods for screening proteins using DNA encoded chemical libraries as templates for enzyme catalysis |
EP3543350B1 (en) | 2012-04-24 | 2021-11-10 | Gen9, Inc. | Methods for sorting nucleic acids and multiplexed preparative in vitro cloning |
IN2014DN09261A (ja) | 2012-04-25 | 2015-07-10 | Regeneron Pharma | |
EP3597741A1 (en) | 2012-04-27 | 2020-01-22 | Duke University | Genetic correction of mutated genes |
MA37663B1 (fr) | 2012-05-25 | 2019-12-31 | Univ California | Procédés et compositions permettant la modification de l'adn cible dirigée par l'arn et la modulation de la transcription dirigée par l'arn |
EP2861737B1 (en) | 2012-06-19 | 2019-04-17 | Regents Of The University Of Minnesota | Gene targeting in plants using dna viruses |
WO2014004393A1 (en) | 2012-06-25 | 2014-01-03 | Gen9, Inc. | Methods for nucleic acid assembly and high throughput sequencing |
CN116622704A (zh) * | 2012-07-25 | 2023-08-22 | 布罗德研究所有限公司 | 可诱导的dna结合蛋白和基因组干扰工具及其应用 |
KR102182847B1 (ko) * | 2012-10-23 | 2020-11-27 | 주식회사 툴젠 | 표적 DNA에 특이적인 가이드 RNA 및 Cas 단백질을 암호화하는 핵산 또는 Cas 단백질을 포함하는, 표적 DNA를 절단하기 위한 조성물 및 이의 용도 |
CN105051204B (zh) | 2012-11-16 | 2023-07-21 | 波赛伊达治疗学股份有限公司 | 位点特异性酶和使用方法 |
EP3617309A3 (en) | 2012-12-06 | 2020-05-06 | Sigma Aldrich Co. LLC | Crispr-based genome modification and regulation |
KR20150105634A (ko) * | 2012-12-12 | 2015-09-17 | 더 브로드 인스티튜트, 인코퍼레이티드 | 서열 조작을 위한 개선된 시스템, 방법 및 효소 조성물의 유전자 조작 및 최적화 |
US8697359B1 (en) * | 2012-12-12 | 2014-04-15 | The Broad Institute, Inc. | CRISPR-Cas systems and methods for altering expression of gene products |
IL293526A (en) * | 2012-12-12 | 2022-08-01 | Harvard College | Providing, engineering and optimizing systems, methods and compositions for sequence manipulation and therapeutic applications |
WO2014093595A1 (en) * | 2012-12-12 | 2014-06-19 | The Broad Institute, Inc. | Crispr-cas component systems, methods and compositions for sequence manipulation |
EP3064585B1 (en) | 2012-12-12 | 2020-02-05 | The Broad Institute, Inc. | Engineering and optimization of improved systems, methods and enzyme compositions for sequence manipulation |
PT2771468E (pt) * | 2012-12-12 | 2015-06-02 | Harvard College | Engenharia de sistemas, métodos e composições-guia otimizadas para manipulação de sequências |
WO2014093709A1 (en) | 2012-12-12 | 2014-06-19 | The Broad Institute, Inc. | Methods, models, systems, and apparatus for identifying target sequences for cas enzymes or crispr-cas systems for target sequences and conveying results thereof |
US20140310830A1 (en) | 2012-12-12 | 2014-10-16 | Feng Zhang | CRISPR-Cas Nickase Systems, Methods And Compositions For Sequence Manipulation in Eukaryotes |
DK2931898T3 (en) | 2012-12-12 | 2016-06-20 | Massachusetts Inst Technology | CONSTRUCTION AND OPTIMIZATION OF SYSTEMS, PROCEDURES AND COMPOSITIONS FOR SEQUENCE MANIPULATION WITH FUNCTIONAL DOMAINS |
ES2741951T3 (es) | 2012-12-17 | 2020-02-12 | Harvard College | Modificación por ingeniería genética del genoma humano guiada por ARN |
JP2016507244A (ja) | 2013-02-27 | 2016-03-10 | ヘルムホルツ・ツェントルム・ミュンヒェン・ドイチェス・フォルシュンクスツェントルム・フューア・ゲズントハイト・ウント・ウムベルト(ゲーエムベーハー)Helmholtz Zentrum MuenchenDeutsches Forschungszentrum fuer Gesundheit und Umwelt (GmbH) | Cas9ヌクレアーゼによる卵母細胞における遺伝子編集 |
EP2971184B1 (en) | 2013-03-12 | 2019-04-17 | President and Fellows of Harvard College | Method of generating a three-dimensional nucleic acid containing matrix |
RU2018122288A (ru) | 2013-03-14 | 2019-03-06 | Карибо Биосайенсиз, Инк. | Композиции и способы с участием нуклеиновых кислот, нацеленных на нуклеиновые кислоты |
AU2014227653B2 (en) | 2013-03-15 | 2017-04-20 | The General Hospital Corporation | Using RNA-guided foki nucleases (RFNs) to increase specificity for RNA-guided genome editing |
US20140273230A1 (en) * | 2013-03-15 | 2014-09-18 | Sigma-Aldrich Co., Llc | Crispr-based genome modification and regulation |
US10760064B2 (en) | 2013-03-15 | 2020-09-01 | The General Hospital Corporation | RNA-guided targeting of genetic and epigenomic regulatory proteins to specific genomic loci |
US20140273235A1 (en) * | 2013-03-15 | 2014-09-18 | Regents Of The University Of Minnesota | ENGINEERING PLANT GENOMES USING CRISPR/Cas SYSTEMS |
SI2986729T1 (sl) | 2013-04-16 | 2019-02-28 | Regeneron Pharmaceuticals, Inc. | Ciljana sprememba genoma podgane |
WO2014172470A2 (en) * | 2013-04-16 | 2014-10-23 | Whitehead Institute For Biomedical Research | Methods of mutating, modifying or modulating nucleic acid in a cell or nonhuman mammal |
CA2910489A1 (en) | 2013-05-15 | 2014-11-20 | Sangamo Biosciences, Inc. | Methods and compositions for treatment of a genetic condition |
US20160122774A1 (en) * | 2013-05-29 | 2016-05-05 | Cellectis | A method for producing precise dna cleavage using cas9 nickase activity |
US20140356956A1 (en) | 2013-06-04 | 2014-12-04 | President And Fellows Of Harvard College | RNA-Guided Transcriptional Regulation |
MY197877A (en) * | 2013-06-04 | 2023-07-22 | Harvard College | Rna-guided transcriptional regulation |
JP7085716B2 (ja) * | 2013-06-05 | 2022-06-17 | デューク ユニバーシティ | Rnaガイド遺伝子編集及び遺伝子調節 |
US20160145631A1 (en) | 2013-06-14 | 2016-05-26 | Cellectis | Methods for non-transgenic genome editing in plants |
EP3725885A1 (en) | 2013-06-17 | 2020-10-21 | The Broad Institute, Inc. | Functional genomics using crispr-cas systems, compositions methods, screens and applications thereof |
SG11201510284XA (en) | 2013-06-17 | 2016-01-28 | Broad Inst Inc | Delivery and use of the crispr-cas systems, vectors and compositions for hepatic targeting and therapy |
ES2767318T3 (es) * | 2013-06-17 | 2020-06-17 | Broad Inst Inc | Suministro, modificación y optimización de sistemas, métodos y composiciones para generar modelos y actuar sobre enfermedades y trastornos de células posmitóticas |
CN106062197A (zh) * | 2013-06-17 | 2016-10-26 | 布罗德研究所有限公司 | 用于序列操纵的串联指导***、方法和组合物的递送、工程化和优化 |
AU2014281027A1 (en) * | 2013-06-17 | 2016-01-28 | Massachusetts Institute Of Technology | Optimized CRISPR-Cas double nickase systems, methods and compositions for sequence manipulation |
EP3011034B1 (en) * | 2013-06-17 | 2019-08-07 | The Broad Institute, Inc. | Delivery, use and therapeutic applications of the crispr-cas systems and compositions for targeting disorders and diseases using viral components |
US10011850B2 (en) | 2013-06-21 | 2018-07-03 | The General Hospital Corporation | Using RNA-guided FokI Nucleases (RFNs) to increase specificity for RNA-Guided Genome Editing |
US11306328B2 (en) * | 2013-07-26 | 2022-04-19 | President And Fellows Of Harvard College | Genome engineering |
US20150044192A1 (en) | 2013-08-09 | 2015-02-12 | President And Fellows Of Harvard College | Methods for identifying a target site of a cas9 nuclease |
US9359599B2 (en) | 2013-08-22 | 2016-06-07 | President And Fellows Of Harvard College | Engineered transcription activator-like effector (TALE) domains and uses thereof |
CA3221516A1 (en) | 2013-08-22 | 2015-02-26 | E. I. Du Pont De Nemours And Company | Plant genome modification using guide rna/cas endonuclease systems and methods of use |
US9322037B2 (en) | 2013-09-06 | 2016-04-26 | President And Fellows Of Harvard College | Cas9-FokI fusion proteins and uses thereof |
US9340800B2 (en) | 2013-09-06 | 2016-05-17 | President And Fellows Of Harvard College | Extended DNA-sensing GRNAS |
US9526784B2 (en) | 2013-09-06 | 2016-12-27 | President And Fellows Of Harvard College | Delivery system for functional nucleases |
ES2844174T3 (es) * | 2013-09-18 | 2021-07-21 | Kymab Ltd | Métodos, células y organismos |
WO2015065964A1 (en) | 2013-10-28 | 2015-05-07 | The Broad Institute Inc. | Functional genomics using crispr-cas systems, compositions, methods, screens and applications thereof |
WO2015066119A1 (en) | 2013-10-30 | 2015-05-07 | North Carolina State University | Compositions and methods related to a type-ii crispr-cas system in lactobacillus buchneri |
CN106459995B (zh) | 2013-11-07 | 2020-02-21 | 爱迪塔斯医药有限公司 | 使用统治型gRNA的CRISPR相关方法和组合物 |
MX2016007654A (es) | 2013-12-11 | 2017-08-15 | Regeneron Pharma | Metodos y composiciones para la modificacion dirigida de un genoma. |
SI3080279T1 (sl) | 2013-12-11 | 2019-01-31 | Regeneron Pharmaceuticals, Inc. | Postopki in sestavki za ciljano spremembo genoma |
BR112016013520A2 (pt) | 2013-12-12 | 2017-10-03 | Broad Inst Inc | Composições e métodos de uso de sistemas crispr-cas em distúrbios de repetições de nucleotídeos |
JP6793547B2 (ja) | 2013-12-12 | 2020-12-02 | ザ・ブロード・インスティテュート・インコーポレイテッド | 最適化機能CRISPR−Cas系による配列操作のための系、方法および組成物 |
KR20160089527A (ko) | 2013-12-12 | 2016-07-27 | 더 브로드 인스티튜트, 인코퍼레이티드 | 게놈 편집을 위한 crispr-cas 시스템 및 조성물의 전달, 용도 및 치료적 응용 |
WO2015089427A1 (en) | 2013-12-12 | 2015-06-18 | The Broad Institute Inc. | Crispr-cas systems and methods for altering expression of gene products, structural information and inducible modular cas enzymes |
WO2015089364A1 (en) | 2013-12-12 | 2015-06-18 | The Broad Institute Inc. | Crystal structure of a crispr-cas system, and uses thereof |
US20150166985A1 (en) | 2013-12-12 | 2015-06-18 | President And Fellows Of Harvard College | Methods for correcting von willebrand factor point mutations |
US10787654B2 (en) * | 2014-01-24 | 2020-09-29 | North Carolina State University | Methods and compositions for sequence guiding Cas9 targeting |
WO2015123339A1 (en) | 2014-02-11 | 2015-08-20 | The Regents Of The University Of Colorado, A Body Corporate | Crispr enabled multiplexed genome engineering |
AU2015219167A1 (en) | 2014-02-18 | 2016-09-08 | Duke University | Compositions for the inactivation of virus replication and methods of making and using the same |
US11028388B2 (en) | 2014-03-05 | 2021-06-08 | Editas Medicine, Inc. | CRISPR/Cas-related methods and compositions for treating Usher syndrome and retinitis pigmentosa |
DK3116997T3 (da) | 2014-03-10 | 2019-08-19 | Editas Medicine Inc | Crispr/cas-relaterede fremgangsmåder og sammensætninger til behandling af lebers kongenitale amaurose 10 (lca10) |
US11339437B2 (en) | 2014-03-10 | 2022-05-24 | Editas Medicine, Inc. | Compositions and methods for treating CEP290-associated disease |
US11141493B2 (en) | 2014-03-10 | 2021-10-12 | Editas Medicine, Inc. | Compositions and methods for treating CEP290-associated disease |
WO2015148670A1 (en) * | 2014-03-25 | 2015-10-01 | Editas Medicine Inc. | Crispr/cas-related methods and compositions for treating hiv infection and aids |
EP3122880B1 (en) | 2014-03-26 | 2021-05-05 | Editas Medicine, Inc. | Crispr/cas-related methods and compositions for treating sickle cell disease |
CN106460003A (zh) | 2014-04-08 | 2017-02-22 | 北卡罗来纳州立大学 | 用于使用crispr相关基因rna引导阻遏转录的方法和组合物 |
WO2015188056A1 (en) * | 2014-06-05 | 2015-12-10 | Sangamo Biosciences, Inc. | Methods and compositions for nuclease design |
CN106795521B (zh) | 2014-06-06 | 2021-06-04 | 瑞泽恩制药公司 | 用于修饰所靶向基因座的方法和组合物 |
CA2952697A1 (en) * | 2014-06-16 | 2015-12-23 | The Johns Hopkins University | Compositions and methods for the expression of crispr guide rnas using the h1 promoter |
US20170107541A1 (en) * | 2014-06-17 | 2017-04-20 | Poseida Therapeutics, Inc. | A method for directing proteins to specific loci in the genome and uses thereof |
EP3354732B1 (en) * | 2014-06-23 | 2020-01-08 | Regeneron Pharmaceuticals, Inc. | Nuclease-mediated dna assembly |
AU2015279642B2 (en) | 2014-06-26 | 2021-03-25 | Regeneron Pharmaceuticals, Inc. | Methods and compositions for targeted genetic modifications and methods of use |
US20170198268A1 (en) * | 2014-07-09 | 2017-07-13 | Gen9, Inc. | Compositions and Methods for Site-Directed DNA Nicking and Cleaving |
CA2954791A1 (en) * | 2014-07-14 | 2016-01-21 | The Regents Of The University Of California | Crispr/cas transcriptional modulation |
EP4079847A1 (en) | 2014-07-30 | 2022-10-26 | President And Fellows Of Harvard College | Cas9 proteins including ligand-dependent inteins |
CN106922154B (zh) * | 2014-08-06 | 2022-01-07 | 基因工具股份有限公司 | 使用空肠弯曲杆菌crispr/cas***衍生的rna引导的工程化核酸酶的基因编辑 |
US10450584B2 (en) | 2014-08-28 | 2019-10-22 | North Carolina State University | Cas9 proteins and guiding features for DNA targeting and genome editing |
EP3188763B1 (en) | 2014-09-02 | 2020-05-13 | The Regents of The University of California | Methods and compositions for rna-directed target dna modification |
WO2016040030A1 (en) | 2014-09-12 | 2016-03-17 | E. I. Du Pont De Nemours And Company | Generation of site-specific-integration sites for complex trait loci in corn and soybean, and methods of use |
CA2963840A1 (en) | 2014-10-09 | 2016-04-14 | Seattle Children's Hospital (dba Seattle Children's Research Institute) | Long poly(a) plasmids and methods for introduction of long poly(a) sequences into the plasmid |
CN107002078A (zh) * | 2014-10-09 | 2017-08-01 | 生命技术公司 | Crispr寡核苷酸和基因剪辑 |
WO2016061374A1 (en) | 2014-10-15 | 2016-04-21 | Regeneron Pharmaceuticals, Inc. | Methods and compositions for generating or maintaining pluripotent cells |
WO2016065364A1 (en) * | 2014-10-24 | 2016-04-28 | Life Technologies Corporation | Compositions and methods for enhancing homologous recombination |
CN107429246B (zh) * | 2014-10-31 | 2021-06-01 | 麻省理工学院 | 用于crispr的大规模并行组合遗传学 |
DK3215611T3 (da) * | 2014-11-06 | 2019-11-25 | Du Pont | Peptid-medieret indgivelse af rna-guidet endonuklease i celler |
EP3215617B1 (en) | 2014-11-07 | 2024-05-08 | Editas Medicine, Inc. | Systems for improving crispr/cas-mediated genome-editing |
WO2016077273A1 (en) * | 2014-11-11 | 2016-05-19 | Q Therapeutics, Inc. | Engineering mesenchymal stem cells using homologous recombination |
JP2017534294A (ja) | 2014-11-19 | 2017-11-24 | インスティチュート フォー ベーシック サイエンスInstitute For Basic Science | 二つのベクターから発現されたcas9タンパク質を利用した遺伝子発現調節方法 |
ES2731437T3 (es) | 2014-11-21 | 2019-11-15 | Regeneron Pharma | Métodos y composiciones para la modificación genética dirigida mediante el uso de pares de ARN guías |
GB201421096D0 (en) | 2014-11-27 | 2015-01-14 | Imp Innovations Ltd | Genome editing methods |
CA2969619A1 (en) | 2014-12-03 | 2016-06-09 | Agilent Technologies, Inc. | Guide rna with chemical modifications |
CN116059378A (zh) | 2014-12-10 | 2023-05-05 | 明尼苏达大学董事会 | 用于治疗疾病的遗传修饰的细胞、组织和器官 |
EP3230451B1 (en) | 2014-12-12 | 2021-04-07 | The Broad Institute, Inc. | Protected guide rnas (pgrnas) |
WO2016100857A1 (en) | 2014-12-19 | 2016-06-23 | Regeneron Pharmaceuticals, Inc. | Stem cells for modeling type 2 diabetes |
EP3232774B1 (en) | 2014-12-19 | 2019-10-09 | Regeneron Pharmaceuticals, Inc. | Methods and compositions for targeted genetic modification through single-step multiple targeting |
US11248240B2 (en) | 2015-01-29 | 2022-02-15 | Meiogenix | Method for inducing targeted meiotic recombinations |
EP3280803B1 (en) | 2015-04-06 | 2021-05-26 | The Board of Trustees of the Leland Stanford Junior University | Chemically modified guide rnas for crispr/cas-mediated gene regulation |
EP3286571B1 (en) | 2015-04-24 | 2021-08-18 | Editas Medicine, Inc. | Evaluation of cas9 molecule/guide rna molecule complexes |
WO2016176617A2 (en) | 2015-04-29 | 2016-11-03 | New York University | Method for treating high-grade gliomas |
EP3292219B9 (en) | 2015-05-04 | 2022-05-18 | Ramot at Tel-Aviv University Ltd. | Methods and kits for fragmenting dna |
AU2016261358B2 (en) | 2015-05-11 | 2021-09-16 | Editas Medicine, Inc. | Optimized CRISPR/Cas9 systems and methods for gene editing in stem cells |
AU2016270649B2 (en) | 2015-05-29 | 2022-04-21 | North Carolina State University | Methods for screening bacteria, archaea, algae, and yeast using crispr nucleic acids |
EP3303585A4 (en) | 2015-06-03 | 2018-10-31 | Board of Regents of the University of Nebraska | Dna editing using single-stranded dna |
WO2016201047A1 (en) | 2015-06-09 | 2016-12-15 | Editas Medicine, Inc. | Crispr/cas-related methods and compositions for improving transplantation |
FI3307872T3 (fi) | 2015-06-15 | 2023-10-16 | Univ North Carolina State | Menetelmiä ja koostumuksia nukleiinihappojen ja rna-pohjaisten antimikrobien tehokkaaseen antamiseen |
AU2016278226B2 (en) * | 2015-06-17 | 2021-08-12 | Poseida Therapeutics, Inc. | Compositions and methods for directing proteins to specific loci in the genome |
EP3129393B1 (en) | 2015-06-18 | 2021-08-04 | The Broad Institute Inc. | Crispr enzyme mutations reducing off-target effects |
WO2016205759A1 (en) | 2015-06-18 | 2016-12-22 | The Broad Institute Inc. | Engineering and optimization of systems, methods, enzymes and guide scaffolds of cas9 orthologs and variants for sequence manipulation |
CN107949400A (zh) * | 2015-06-24 | 2018-04-20 | 西格马-奥尔德里奇有限责任公司 | 细胞周期依赖性基因组调控和修饰 |
US20170119820A1 (en) | 2015-07-31 | 2017-05-04 | Regents Of The University Of Minnesota | Modified cells and methods of therapy |
US10709726B2 (en) | 2015-08-14 | 2020-07-14 | The University Of Sydney | Connexin 45 inhibition for therapy |
IL288662B2 (en) | 2015-08-25 | 2023-09-01 | Univ Duke | Preparations and methods for improving specificity in genomic engineering using RNA-guided endonucleases |
WO2017040348A1 (en) | 2015-08-28 | 2017-03-09 | The General Hospital Corporation | Engineered crispr-cas9 nucleases |
US9512446B1 (en) | 2015-08-28 | 2016-12-06 | The General Hospital Corporation | Engineered CRISPR-Cas9 nucleases |
US9926546B2 (en) | 2015-08-28 | 2018-03-27 | The General Hospital Corporation | Engineered CRISPR-Cas9 nucleases |
US11667911B2 (en) | 2015-09-24 | 2023-06-06 | Editas Medicine, Inc. | Use of exonucleases to improve CRISPR/CAS-mediated genome editing |
KR101745863B1 (ko) | 2015-09-25 | 2017-06-12 | 전남대학교산학협력단 | Crispr/cas9 시스템을 이용한 프로히비틴2 유전자 제거용 시발체 |
KR101795999B1 (ko) | 2015-09-25 | 2017-11-09 | 전남대학교산학협력단 | Crispr/cas9 시스템을 이용한 베타2-마이크로글로불린 유전자 제거용 시발체 |
US11286480B2 (en) | 2015-09-28 | 2022-03-29 | North Carolina State University | Methods and compositions for sequence specific antimicrobials |
EP3362571A4 (en) * | 2015-10-13 | 2019-07-10 | Duke University | GENOMIC ENGINEERING WITH TYPE I CRISPRISMS IN EUKARYOTIC CELLS |
CN108370303B (zh) | 2015-10-22 | 2022-03-08 | 瑞典爱立信有限公司 | 与无线电信号的选择性增强有关的方法和设备 |
JP7067793B2 (ja) * | 2015-10-23 | 2022-05-16 | プレジデント アンド フェローズ オブ ハーバード カレッジ | 核酸塩基編集因子およびその使用 |
US20180230489A1 (en) | 2015-10-28 | 2018-08-16 | Voyager Therapeutics, Inc. | Regulatable expression using adeno-associated virus (aav) |
GB2559526B (en) | 2015-11-03 | 2021-02-17 | Harvard College | Method and apparatus for volumetric imaging of a three-dimensional nucleic acid containing matrix |
US11905521B2 (en) | 2015-11-17 | 2024-02-20 | The Chinese University Of Hong Kong | Methods and systems for targeted gene manipulation |
US10240145B2 (en) * | 2015-11-25 | 2019-03-26 | The Board Of Trustees Of The Leland Stanford Junior University | CRISPR/Cas-mediated genome editing to treat EGFR-mutant lung cancer |
US11542466B2 (en) | 2015-12-22 | 2023-01-03 | North Carolina State University | Methods and compositions for delivery of CRISPR based antimicrobials |
IL260532B2 (en) | 2016-01-11 | 2023-12-01 | Univ Leland Stanford Junior | Systems containing chaperone proteins and their uses for controlling gene expression |
EA201891614A1 (ru) | 2016-01-11 | 2019-02-28 | Те Борд Оф Трастиз Оф Те Лилэнд Стэнфорд Джуниор Юниверсити | Химерные белки и способы иммунотерапии |
EP3219799A1 (en) | 2016-03-17 | 2017-09-20 | IMBA-Institut für Molekulare Biotechnologie GmbH | Conditional crispr sgrna expression |
US11597924B2 (en) | 2016-03-25 | 2023-03-07 | Editas Medicine, Inc. | Genome editing systems comprising repair-modulating enzyme molecules and methods of their use |
US11512311B2 (en) | 2016-03-25 | 2022-11-29 | Editas Medicine, Inc. | Systems and methods for treating alpha 1-antitrypsin (A1AT) deficiency |
EP3443086B1 (en) | 2016-04-13 | 2021-11-24 | Editas Medicine, Inc. | Cas9 fusion molecules, gene editing systems, and methods of use thereof |
WO2017180926A1 (en) * | 2016-04-14 | 2017-10-19 | Boco Silicon Valley. Inc. | Genome editing of human neural stem cells using nucleases |
EP3449016A4 (en) | 2016-04-25 | 2019-10-02 | President and Fellows of Harvard College | HYBRIDIZATION CHAIN REACTION PROCESS FOR IN-SITU MOLECULE DETECTION |
WO2017186718A1 (en) * | 2016-04-25 | 2017-11-02 | Universität Basel | Allele editing and applications thereof |
KR102661748B1 (ko) | 2016-05-20 | 2024-05-31 | 리제너론 파마슈티칼스 인코포레이티드 | 다중 가이드 RNAs를 이용한 면역학적 내성 파괴 방법 |
KR102458395B1 (ko) * | 2016-06-02 | 2022-10-25 | 시그마-알드리치 컴퍼니., 엘엘씨 | 프로그램가능한 dna 결합 단백질을 사용한, 표적화된 게놈 변형의 개선 |
AU2017277810A1 (en) * | 2016-06-03 | 2018-12-06 | Temple University - Of The Commonwealth System Of Higher Education | Negative feedback regulation of HIV-1 by gene editing strategy |
CA3025591A1 (en) * | 2016-06-03 | 2017-12-07 | Philippe Ravassard | Diet controlled expression of a nucleic acid encoding cas9 nuclease and uses thereof |
US10767175B2 (en) | 2016-06-08 | 2020-09-08 | Agilent Technologies, Inc. | High specificity genome editing using chemically modified guide RNAs |
US10337051B2 (en) | 2016-06-16 | 2019-07-02 | The Regents Of The University Of California | Methods and compositions for detecting a target RNA |
US11293021B1 (en) | 2016-06-23 | 2022-04-05 | Inscripta, Inc. | Automated cell processing methods, modules, instruments, and systems |
EP3474669B1 (en) | 2016-06-24 | 2022-04-06 | The Regents of The University of Colorado, A Body Corporate | Methods for generating barcoded combinatorial libraries |
US11603533B2 (en) | 2016-07-12 | 2023-03-14 | Washington University | Incorporation of internal polya-encoded poly-lysine sequence tags and their variations for the tunable control of protein synthesis in bacterial and eukaryotic cells |
AU2017302611B2 (en) | 2016-07-28 | 2021-12-09 | Regeneron Pharmaceuticals, Inc. | GPR156 variants and uses thereof |
BR112019001783A2 (pt) | 2016-07-29 | 2019-05-07 | Regeneron Pharmaceuticals, Inc. | mamífero não humano, e, métodos para produzir o mamífero não humano e de triagem de um composto. |
CA3032822A1 (en) | 2016-08-02 | 2018-02-08 | Editas Medicine, Inc. | Compositions and methods for treating cep290 associated disease |
US11078481B1 (en) | 2016-08-03 | 2021-08-03 | KSQ Therapeutics, Inc. | Methods for screening for cancer targets |
KR102547316B1 (ko) | 2016-08-03 | 2023-06-23 | 프레지던트 앤드 펠로우즈 오브 하바드 칼리지 | 아데노신 핵염기 편집제 및 그의 용도 |
US11661590B2 (en) | 2016-08-09 | 2023-05-30 | President And Fellows Of Harvard College | Programmable CAS9-recombinase fusion proteins and uses thereof |
JP2019524149A (ja) * | 2016-08-20 | 2019-09-05 | アベリノ ラボ ユーエスエー インコーポレイテッドAvellino Lab USA, Inc. | 一本鎖ガイドRNA、CRISPR/Cas9システム、及びそれらの使用方法 |
US11542509B2 (en) | 2016-08-24 | 2023-01-03 | President And Fellows Of Harvard College | Incorporation of unnatural amino acids into proteins using base editing |
US11078483B1 (en) | 2016-09-02 | 2021-08-03 | KSQ Therapeutics, Inc. | Methods for measuring and improving CRISPR reagent function |
US20180105806A1 (en) * | 2016-09-07 | 2018-04-19 | Massachusetts Institute Of Technology | Method for rna-guided endonuclease-based dna assembly |
CN106636197B (zh) * | 2016-09-22 | 2019-09-03 | 南京市妇幼保健院 | 一种定向敲降斑马鱼基因组中多拷贝基因的方法 |
US20190225974A1 (en) | 2016-09-23 | 2019-07-25 | BASF Agricultural Solutions Seed US LLC | Targeted genome optimization in plants |
MX2019003674A (es) | 2016-09-30 | 2021-01-08 | Univ California | Enzimas modificadoras de ácido nucleico guiadas por arn y métodos de uso de estas. |
US20190233820A1 (en) * | 2016-10-11 | 2019-08-01 | Stemgenics, Inc. | Nanoparticles functionalized with gene editing tools and related methods |
US11306324B2 (en) | 2016-10-14 | 2022-04-19 | President And Fellows Of Harvard College | AAV delivery of nucleobase editors |
WO2018071892A1 (en) | 2016-10-14 | 2018-04-19 | Joung J Keith | Epigenetically regulated site-specific nucleases |
GB201617559D0 (en) | 2016-10-17 | 2016-11-30 | University Court Of The University Of Edinburgh The | Swine comprising modified cd163 and associated methods |
GB2573406B (en) | 2016-10-18 | 2021-11-10 | Univ Minnesota | Tumor infiltrating lymphocytes and methods of therapy |
KR20190072639A (ko) * | 2016-11-02 | 2019-06-25 | 유니버시타트 바셀 | 세포 치료에 사용하기 위한 면역학적으로 식별 가능한 세포 표면 변이체 |
US10745677B2 (en) | 2016-12-23 | 2020-08-18 | President And Fellows Of Harvard College | Editing of CCR5 receptor gene to protect against HIV infection |
KR102151065B1 (ko) * | 2016-12-23 | 2020-09-02 | 기초과학연구원 | 동물 배아의 염기 교정용 조성물 및 염기 교정 방법 |
US11859219B1 (en) | 2016-12-30 | 2024-01-02 | Flagship Pioneering Innovations V, Inc. | Methods of altering a target nucleotide sequence with an RNA-guided nuclease and a single guide RNA |
KR20190111067A (ko) | 2017-01-23 | 2019-10-01 | 리제너론 파마슈티칼스 인코포레이티드 | 하이드록시스테로이드 17-베타 탈수소효소 13 (hsd17b13) 변이체 및 이의 용도 |
TW201839136A (zh) | 2017-02-06 | 2018-11-01 | 瑞士商諾華公司 | 治療血色素異常症之組合物及方法 |
CN106978438B (zh) * | 2017-02-27 | 2020-08-28 | 北京大北农生物技术有限公司 | 提高同源重组效率的方法 |
WO2018165504A1 (en) | 2017-03-09 | 2018-09-13 | President And Fellows Of Harvard College | Suppression of pain by gene editing |
EP3592777A1 (en) | 2017-03-10 | 2020-01-15 | President and Fellows of Harvard College | Cytosine to guanine base editor |
EP3596217A1 (en) | 2017-03-14 | 2020-01-22 | Editas Medicine, Inc. | Systems and methods for the treatment of hemoglobinopathies |
IL306092A (en) | 2017-03-23 | 2023-11-01 | Harvard College | Nucleic base editors that include nucleic acid programmable DNA binding proteins |
WO2018195129A1 (en) | 2017-04-17 | 2018-10-25 | University Of Maryland, College Park | Embryonic cell cultures and methods of using the same |
US11834670B2 (en) | 2017-04-19 | 2023-12-05 | Global Life Sciences Solutions Usa Llc | Site-specific DNA modification using a donor DNA repair template having tandem repeat sequences |
CN110799525A (zh) | 2017-04-21 | 2020-02-14 | 通用医疗公司 | 具有改变的PAM特异性的CPF1(CAS12a)的变体 |
EP3615672A1 (en) | 2017-04-28 | 2020-03-04 | Editas Medicine, Inc. | Methods and systems for analyzing guide rna molecules |
EP3622070A2 (en) | 2017-05-10 | 2020-03-18 | Editas Medicine, Inc. | Crispr/rna-guided nuclease systems and methods |
WO2018209320A1 (en) | 2017-05-12 | 2018-11-15 | President And Fellows Of Harvard College | Aptazyme-embedded guide rnas for use with crispr-cas9 in genome editing and transcriptional activation |
CA3063449A1 (en) | 2017-05-25 | 2018-11-29 | The General Hospital Corporation | Using split deaminases to limit unwanted off-target base editor deamination |
CA3065938A1 (en) | 2017-06-05 | 2018-12-13 | Regeneron Pharmaceuticals, Inc. | B4galt1 variants and uses thereof |
US10428319B2 (en) | 2017-06-09 | 2019-10-01 | Editas Medicine, Inc. | Engineered Cas9 nucleases |
CA3067382A1 (en) | 2017-06-15 | 2018-12-20 | The Regents Of The University Of California | Targeted non-viral dna insertions |
US10011849B1 (en) | 2017-06-23 | 2018-07-03 | Inscripta, Inc. | Nucleic acid-guided nucleases |
US9982279B1 (en) | 2017-06-23 | 2018-05-29 | Inscripta, Inc. | Nucleic acid-guided nucleases |
AU2018295358A1 (en) | 2017-06-27 | 2020-01-16 | Regeneron Pharmaceuticals, Inc. | Non-human animals comprising a humanized ASGR1 locus |
RU2755308C2 (ru) | 2017-06-30 | 2021-09-15 | Инскрипта, Инк. | Автоматизированный многомодульный инструмент для редактирования клеток (варианты) |
EP3645021A4 (en) | 2017-06-30 | 2021-04-21 | Intima Bioscience, Inc. | ADENO-ASSOCIATED VIRAL VECTORS FOR GENE THERAPY |
US11866726B2 (en) | 2017-07-14 | 2024-01-09 | Editas Medicine, Inc. | Systems and methods for targeted integration and genome editing and detection thereof using integrated priming sites |
CN111801345A (zh) | 2017-07-28 | 2020-10-20 | 哈佛大学的校长及成员们 | 使用噬菌体辅助连续进化(pace)的进化碱基编辑器的方法和组合物 |
RU2019143568A (ru) | 2017-07-31 | 2021-09-02 | Регенерон Фармасьютикалс, Инк. | Способы и композиции для оценки crispr/cas-индуцированной рекомбинации с экзогенной донорной нуклеиновой кислотой in vivo |
BR112020001996A2 (pt) | 2017-07-31 | 2020-08-18 | Regeneron Pharmaceuticals, Inc. | animal não humano, e, métodos para testar e para otimizar a capacidade de uma crispr/cas nuclease de excisar um ácido nucleico genômico in vivo, para testar a recombinação induzida por crispr/cas de um ácido nucleico genômico com um ácido nucleico de doador exógeno in vivo e para otimizar a capacidade de crispr/cas de induzir a recombinação de um ácido nucleico genômico com um ácido nucleico de doador exógeno in vivo. |
AU2018311695A1 (en) * | 2017-07-31 | 2020-01-16 | Sigma-Aldrich Co. Llc | Synthetic guide RNA for CRISPR/Cas activator systems |
BR112020001364A2 (pt) | 2017-07-31 | 2020-08-11 | Regeneron Pharmaceuticals, Inc. | métodos para testar e modificar a capacidade de uma crispr/cas nuclease. |
WO2019030695A1 (en) * | 2017-08-09 | 2019-02-14 | Benson Hill Biosystems, Inc. | COMPOSITIONS AND METHODS FOR MODIFYING GENOMES |
US10738327B2 (en) | 2017-08-28 | 2020-08-11 | Inscripta, Inc. | Electroporation cuvettes for automation |
US11319532B2 (en) | 2017-08-30 | 2022-05-03 | President And Fellows Of Harvard College | High efficiency base editors comprising Gam |
EP3678680A4 (en) * | 2017-09-05 | 2021-12-01 | Regeneron Pharmaceuticals, Inc. | ADMINISTRATION OF A GENE EDITING SYSTEM CONTAINING A SINGLE RETROVIRAL PARTICLE AND METHODS OF GENERATION AND USE |
CN111373053A (zh) | 2017-09-06 | 2020-07-03 | 雷杰纳荣制药公司 | 单免疫球蛋白白介素-1受体相关分子(sigirr)变体及其用途 |
CN111278851A (zh) | 2017-09-07 | 2020-06-12 | 雷杰纳荣制药公司 | 溶质运载体家族14成员1(slc14a1)变体及其用途 |
NZ761329A (en) | 2017-09-29 | 2023-04-28 | Regeneron Pharma | Non-human animals comprising a humanized ttr locus and methods of use |
WO2019068022A1 (en) | 2017-09-30 | 2019-04-04 | Inscripta, Inc. | CONTINUOUS FLOW ELECTROPORATION INSTRUMENTATION |
WO2019079195A1 (en) * | 2017-10-16 | 2019-04-25 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | GENETICALLY MODIFIED MESENCHYMAL STEM CELLS FOR USE IN CARDIOVASCULAR PROSTHESES |
JP2021500036A (ja) | 2017-10-16 | 2021-01-07 | ザ ブロード インスティテュート, インコーポレーテッドThe Broad Institute, Inc. | アデノシン塩基編集因子の使用 |
SG11202002822XA (en) | 2017-10-16 | 2020-04-29 | Regeneron Pharma | Cornulin (crnn) variants and uses thereof |
CA3080415A1 (en) | 2017-10-27 | 2019-05-02 | The Regents Of The University Of California | Targeted replacement of endogenous t cell receptors |
WO2019089808A1 (en) | 2017-11-01 | 2019-05-09 | The Regents Of The University Of California | Class 2 crispr/cas compositions and methods of use |
CA3076371C (en) | 2017-11-10 | 2022-11-22 | Regeneron Pharmaceuticals, Inc. | Non-human animals comprising slc30a8 mutation and methods of use |
US20210180059A1 (en) * | 2017-11-16 | 2021-06-17 | Astrazeneca Ab | Compositions and methods for improving the efficacy of cas9-based knock-in strategies |
IL274740B2 (en) | 2017-11-30 | 2024-06-01 | Regeneron Pharma | Non-human animals containing a human TRKB locus |
WO2019126578A1 (en) * | 2017-12-20 | 2019-06-27 | Poseida Therapeutics, Inc. | Compositions and methods for directing proteins to specific loci in the genome |
KR102098915B1 (ko) * | 2017-12-22 | 2020-04-09 | (주)지플러스 생명과학 | 키메라 게놈 조작 분자 및 방법 |
CN111566121A (zh) | 2018-01-12 | 2020-08-21 | 巴斯夫欧洲公司 | 小麦7a染色体上决定每穗小穗数QTL的基因 |
WO2019147302A1 (en) * | 2018-01-26 | 2019-08-01 | Bauer Daniel E | Targeting bcl11a distal regulatory elements with a cas9-cas9 fusion for fetal hemoglobin reinduction |
KR102494449B1 (ko) | 2018-02-15 | 2023-01-31 | 시그마-알드리치 컴퍼니., 엘엘씨 | 진핵 게놈 변형을 위한 조작된 cas9 시스템 |
KR20240038811A (ko) | 2018-03-19 | 2024-03-25 | 리제너론 파마슈티칼스 인코포레이티드 | CRISPR/Cas 시스템을 사용한 동물에서의 전사 조절 |
CN112204131A (zh) | 2018-03-29 | 2021-01-08 | 因思科瑞普特公司 | 用于诱导和转化的细胞生长速率的自动化控制 |
WO2019200004A1 (en) | 2018-04-13 | 2019-10-17 | Inscripta, Inc. | Automated cell processing instruments comprising reagent cartridges |
SG11202009783WA (en) | 2018-04-19 | 2020-11-27 | Univ California | Compositions and methods for gene editing |
US10858761B2 (en) | 2018-04-24 | 2020-12-08 | Inscripta, Inc. | Nucleic acid-guided editing of exogenous polynucleotides in heterologous cells |
US10526598B2 (en) | 2018-04-24 | 2020-01-07 | Inscripta, Inc. | Methods for identifying T-cell receptor antigens |
WO2019209926A1 (en) | 2018-04-24 | 2019-10-31 | Inscripta, Inc. | Automated instrumentation for production of peptide libraries |
KR20210005178A (ko) * | 2018-04-27 | 2021-01-13 | 시애틀 칠드런즈 호스피탈 디/비/에이 시애틀 칠드런즈 리서치 인스티튜트 | X-연관 고 igm 증후군에서의 치료적 게놈 편집 |
WO2019217803A1 (en) | 2018-05-10 | 2019-11-14 | Auxolytic Ltd. | Gene therapy methods and compositions using auxotrophic regulatable cells |
CN112105732A (zh) * | 2018-05-10 | 2020-12-18 | 先正达参股股份有限公司 | 用于多核苷酸的靶向编辑的方法和组合物 |
CN108624622A (zh) * | 2018-05-16 | 2018-10-09 | 湖南艾佳生物科技股份有限公司 | 一种基于CRISPR-Cas9***构建的能分泌小鼠白细胞介素-6的基因工程细胞株 |
JP2021523745A (ja) | 2018-05-16 | 2021-09-09 | シンテゴ コーポレイション | ガイドrna設計および使用のための方法およびシステム |
EP3575402A1 (en) * | 2018-06-01 | 2019-12-04 | Algentech SAS | Gene targeting |
CA3102975A1 (en) | 2018-06-07 | 2019-12-12 | The State Of Israel, Ministry Of Agriculture & Rural Development, Agricultural Research Organization (Aro) (Volcani Center) | Methods of regenerating and transforming cannabis |
WO2019234754A1 (en) | 2018-06-07 | 2019-12-12 | The State Of Israel, Ministry Of Agriculture & Rural Development, Agricultural Research Organization (Aro) (Volcani Center) | Nucleic acid constructs and methods of using same |
CA3104649A1 (en) * | 2018-06-25 | 2020-12-21 | Bionano Genomics, Inc. | Labeling of dna |
EP3813974A4 (en) | 2018-06-30 | 2022-08-03 | Inscripta, Inc. | INSTRUMENTS, MODULES AND METHODS FOR ENHANCED DETECTION OF EDITED SEQUENCES IN LIVING CELLS |
CN112805379A (zh) * | 2018-08-03 | 2021-05-14 | 比姆医疗股份有限公司 | 多效应核碱基编辑器和使用其修饰核酸靶序列的方法 |
GB201813011D0 (en) | 2018-08-10 | 2018-09-26 | Vib Vzw | Means and methods for drought tolerance in crops |
US10752874B2 (en) | 2018-08-14 | 2020-08-25 | Inscripta, Inc. | Instruments, modules, and methods for improved detection of edited sequences in live cells |
US10532324B1 (en) | 2018-08-14 | 2020-01-14 | Inscripta, Inc. | Instruments, modules, and methods for improved detection of edited sequences in live cells |
US11142740B2 (en) | 2018-08-14 | 2021-10-12 | Inscripta, Inc. | Detection of nuclease edited sequences in automated modules and instruments |
KR102103103B1 (ko) * | 2018-08-16 | 2020-04-21 | (주)라트바이오 | 인위적 뉴클레아제를 생산하는 형질전환 동물 및 형질전환 배아 |
SG11202101382VA (en) * | 2018-08-21 | 2021-03-30 | Sigma Aldrich Co Llc | Down-regulation of the cytosolic dna sensor pathway |
WO2020081149A2 (en) | 2018-08-30 | 2020-04-23 | Inscripta, Inc. | Improved detection of nuclease edited sequences in automated modules and instruments |
CN109055379B (zh) * | 2018-09-10 | 2022-04-15 | 石铭 | 一种转基因鸡输卵管生物反应器的制备方法 |
KR102121817B1 (ko) * | 2018-09-12 | 2020-06-26 | 한국화학연구원 | Crispr 편집 기술을 이용한 재조합 항원을 발현시키는 벡터 및 이를 동시에 다중 삽입시키는 방법 |
US20220053741A1 (en) | 2018-09-13 | 2022-02-24 | Regeneron Pharmaceuticals, Inc. | Complement Factor H Gene Knockout Rat as a Model of C3 Glomerulopathy |
EP3861120A4 (en) | 2018-10-01 | 2023-08-16 | North Carolina State University | RECOMBINANT TYPE I CRISPR-CAS SYSTEM |
GB2611929B (en) | 2018-10-16 | 2023-11-22 | Blueallele Corp | Methods for targeted insertion of DNA in genes |
AU2019368215B2 (en) | 2018-10-22 | 2023-05-18 | Inscripta, Inc. | Engineered enzymes |
US11214781B2 (en) | 2018-10-22 | 2022-01-04 | Inscripta, Inc. | Engineered enzyme |
WO2020086908A1 (en) * | 2018-10-24 | 2020-04-30 | The Broad Institute, Inc. | Constructs for improved hdr-dependent genomic editing |
KR20200071198A (ko) | 2018-12-10 | 2020-06-19 | 네오이뮨텍, 인코퍼레이티드 | Nrf2 발현 조절 기반 T 세포 항암면역치료법 |
CA3117228A1 (en) | 2018-12-14 | 2020-06-18 | Pioneer Hi-Bred International, Inc. | Novel crispr-cas systems for genome editing |
CA3124039A1 (en) | 2018-12-19 | 2020-06-25 | King's College London | Immunotherapeutic methods and compositions |
IL301193A (en) | 2018-12-20 | 2023-05-01 | Regeneron Pharma | Nuclease-mediated repeat expansion |
MX2021008153A (es) * | 2019-01-04 | 2021-08-11 | Univ Chicago | Sistemas y metodos para modular arn. |
WO2020146899A1 (en) * | 2019-01-11 | 2020-07-16 | Chan Zuckerberg Biohub, Inc. | Targeted in vivo genome modification |
US11946040B2 (en) | 2019-02-04 | 2024-04-02 | The General Hospital Corporation | Adenine DNA base editor variants with reduced off-target RNA editing |
US20220298494A1 (en) * | 2019-02-14 | 2022-09-22 | Metagenomi Ip Technologies, Llc | Enzymes with ruvc domains |
JP2022520104A (ja) * | 2019-02-15 | 2022-03-28 | シグマ-アルドリッチ・カンパニー・リミテッド・ライアビリティ・カンパニー | Crispr/cas融合タンパク質およびシステム |
GB201902277D0 (en) | 2019-02-19 | 2019-04-03 | King S College London | Therapeutic agents |
MX2021010559A (es) | 2019-03-07 | 2021-12-15 | Univ California | Polipéptidos efectores de crispr-cas y métodos de uso de estos. |
IL286357B1 (en) | 2019-03-18 | 2024-06-01 | Regeneron Pharma | A CRISPR/CAS screening platform to identify genetic modifiers of tau seeding or aggregation |
SG11202108090XA (en) | 2019-03-18 | 2021-08-30 | Regeneron Pharma | Crispr/cas dropout screening platform to reveal genetic vulnerabilities associated with tau aggregation |
AU2020242032A1 (en) | 2019-03-19 | 2021-10-07 | Massachusetts Institute Of Technology | Methods and compositions for editing nucleotide sequences |
EP3947691A4 (en) | 2019-03-25 | 2022-12-14 | Inscripta, Inc. | SIMULTANEOUS MULTIPLEX GENOME EDITING IN A YEAST |
US11001831B2 (en) | 2019-03-25 | 2021-05-11 | Inscripta, Inc. | Simultaneous multiplex genome editing in yeast |
BR112021019512A2 (pt) | 2019-04-03 | 2022-02-15 | Regeneron Pharma | Métodos para inserir uma sequência de codificação de proteína de ligação ao antígeno e para tratar ou efetuar a profilaxia de uma doença em um animal, animal, célula, genoma, ácido nucleico doador exógeno, gene de porto seguro, e, agente de nuclease ou um ou mais ácidos nucleicos |
IL286917B (en) | 2019-04-04 | 2022-09-01 | Regeneron Pharma | Methods for scar-free insertion of targeted modifications into targeted vectors |
ES2966625T3 (es) | 2019-04-04 | 2024-04-23 | Regeneron Pharma | Roedores que comprenden un locus del factor de coagulación 12 humanizado |
GB201905360D0 (en) | 2019-04-16 | 2019-05-29 | Univ Nottingham | Fungal strains, production and uses thereof |
AU2020274594A1 (en) | 2019-05-10 | 2022-01-20 | Basf Se | Regulatory nucleic acid molecules for enhancing gene expression in plants |
AU2020286382A1 (en) | 2019-06-04 | 2021-11-04 | Regeneron Pharmaceuticals, Inc. | Non-human animals comprising a humanized TTR locus with a beta-slip mutation and methods of use |
CN113939593A (zh) | 2019-06-06 | 2022-01-14 | 因思科瑞普特公司 | 用于递归的核酸指导的细胞编辑的处治 |
EP3796776A1 (en) | 2019-06-07 | 2021-03-31 | Regeneron Pharmaceuticals, Inc. | Non-human animals comprising a humanized albumin locus |
US11845957B2 (en) | 2019-06-14 | 2023-12-19 | Regeneron Pharmaceuticals, Inc. | Models of tauopathy |
US10907125B2 (en) | 2019-06-20 | 2021-02-02 | Inscripta, Inc. | Flow through electroporation modules and instrumentation |
AU2020297499A1 (en) | 2019-06-21 | 2022-02-03 | Inscripta, Inc. | Genome-wide rationally-designed mutations leading to enhanced lysine production in E. coli |
US10927385B2 (en) | 2019-06-25 | 2021-02-23 | Inscripta, Inc. | Increased nucleic-acid guided cell editing in yeast |
WO2021050398A1 (en) * | 2019-09-10 | 2021-03-18 | The Regents Of The University Of California | Synthetic lethality screening platform for cells undergoing alt |
EP4028530A1 (en) | 2019-09-12 | 2022-07-20 | Basf Se | Regulatory nucleic acid molecules for enhancing gene expression in plants |
US20210079394A1 (en) | 2019-09-13 | 2021-03-18 | Regeneron Pharmaceuticals, Inc. | Transcription modulation in animals using crispr/cas systems delivered by lipid nanoparticles |
WO2021069387A1 (en) | 2019-10-07 | 2021-04-15 | Basf Se | Regulatory nucleic acid molecules for enhancing gene expression in plants |
CN110628825A (zh) * | 2019-10-14 | 2019-12-31 | 上海捷易生物科技有限公司 | 一种依赖nhej的报告基因敲入组合物及其使用方法 |
BR112022008861A2 (pt) | 2019-11-08 | 2022-08-23 | Regeneron Pharma | Construto de ácido nucleico, vetor, nanopartícula lipídica, célula, composição para uso na expressão de retinosquisina, método para integrar uma sequência de codificação, e, método para modificar um gene rs1 |
WO2021102059A1 (en) | 2019-11-19 | 2021-05-27 | Inscripta, Inc. | Methods for increasing observed editing in bacteria |
WO2021108363A1 (en) | 2019-11-25 | 2021-06-03 | Regeneron Pharmaceuticals, Inc. | Crispr/cas-mediated upregulation of humanized ttr allele |
AU2020396138A1 (en) | 2019-12-03 | 2022-06-16 | Basf Se | Regulatory nucleic acid molecules for enhancing gene expression in plants |
WO2021118626A1 (en) | 2019-12-10 | 2021-06-17 | Inscripta, Inc. | Novel mad nucleases |
US10704033B1 (en) | 2019-12-13 | 2020-07-07 | Inscripta, Inc. | Nucleic acid-guided nucleases |
KR20220116485A (ko) | 2019-12-16 | 2022-08-23 | 바스프 아그리컬쳐럴 솔루션즈 시드 유에스 엘엘씨 | 쌍을 형성한 닉카제를 이용하는 개선된 게놈 편집 |
EP4069851A4 (en) | 2019-12-18 | 2023-11-22 | Inscripta, Inc. | CASCADE/DCAS3 COMPLEMENTATION ASSAYS FOR IN VIVO DETECTION OF NUCLEIC ACID-GUIDED NUCLEASE-MODIFIED CELLS |
BR112022013772A2 (pt) * | 2020-01-09 | 2022-10-11 | Pioneer Hi Bred Int | Troca de genes em duas etapas |
US10689669B1 (en) | 2020-01-11 | 2020-06-23 | Inscripta, Inc. | Automated multi-module cell processing methods, instruments, and systems |
EP4096770A1 (en) | 2020-01-27 | 2022-12-07 | Inscripta, Inc. | Electroporation modules and instrumentation |
EP4096396A1 (en) | 2020-01-28 | 2022-12-07 | Regeneron Pharmaceuticals, Inc. | Non-human animals comprising a humanized pnpla3 locus and methods of use |
EP4099821A1 (en) | 2020-02-07 | 2022-12-14 | Regeneron Pharmaceuticals, Inc. | <smallcaps/>? ? ?klkb1? ? ? ? ?non-human animals comprising a humanizedlocus and methods of use |
AU2021232598A1 (en) | 2020-03-04 | 2022-09-08 | Regeneron Pharmaceuticals, Inc. | Methods and compositions for sensitization of tumor cells to immune therapy |
US20230102342A1 (en) | 2020-03-23 | 2023-03-30 | Regeneron Pharmaceuticals, Inc. | Non-human animals comprising a humanized ttr locus comprising a v30m mutation and methods of use |
EP4127156A4 (en) | 2020-03-31 | 2024-03-27 | Metagenomi Inc | CLASS II TYPE II CRISPR SYSTEMS |
WO2021202938A1 (en) | 2020-04-03 | 2021-10-07 | Creyon Bio, Inc. | Oligonucleotide-based machine learning |
US20210332388A1 (en) | 2020-04-24 | 2021-10-28 | Inscripta, Inc. | Compositions, methods, modules and instruments for automated nucleic acid-guided nuclease editing in mammalian cells |
BR112022022603A2 (pt) | 2020-05-08 | 2023-01-17 | Broad Inst Inc | Métodos e composições para edição simultânea de ambas as fitas de sequência alvo de nucleotídeos de fita dupla |
US11787841B2 (en) | 2020-05-19 | 2023-10-17 | Inscripta, Inc. | Rationally-designed mutations to the thrA gene for enhanced lysine production in E. coli |
WO2021263146A2 (en) | 2020-06-26 | 2021-12-30 | Regeneron Pharmaceuticals, Inc. | Non-human animals comprising a humanized ace2 locus |
CN111849986A (zh) * | 2020-07-24 | 2020-10-30 | 江苏集萃药康生物科技有限公司 | 一种减少CRISPR-Cas9基因编辑中双链DNA片段串联的方法及其应用 |
US11299731B1 (en) | 2020-09-15 | 2022-04-12 | Inscripta, Inc. | CRISPR editing to embed nucleic acid landing pads into genomes of live cells |
US11512297B2 (en) | 2020-11-09 | 2022-11-29 | Inscripta, Inc. | Affinity tag for recombination protein recruitment |
WO2022120022A1 (en) | 2020-12-02 | 2022-06-09 | Regeneron Pharmaceuticals, Inc. | Crispr sam biosensor cell lines and methods of use thereof |
WO2022133139A2 (en) * | 2020-12-16 | 2022-06-23 | Administrators Of The Tulane Educational Fund | Wnt+ adipocytes, exosomes from wnt+ adipocyte, and methods of making and using them |
US11306298B1 (en) | 2021-01-04 | 2022-04-19 | Inscripta, Inc. | Mad nucleases |
US11332742B1 (en) | 2021-01-07 | 2022-05-17 | Inscripta, Inc. | Mad nucleases |
US11884924B2 (en) | 2021-02-16 | 2024-01-30 | Inscripta, Inc. | Dual strand nucleic acid-guided nickase editing |
GB202103131D0 (en) | 2021-03-05 | 2021-04-21 | Biosystems Tech Limited | Method for preparation of research organisms |
EP4337769A1 (en) | 2021-05-10 | 2024-03-20 | SQZ Biotechnologies Company | Methods for delivering genome editing molecules to the nucleus or cytosol of a cell and uses thereof |
WO2022251644A1 (en) | 2021-05-28 | 2022-12-01 | Lyell Immunopharma, Inc. | Nr4a3-deficient immune cells and uses thereof |
AU2022286947A1 (en) | 2021-06-02 | 2023-12-14 | Lyell Immunopharma, Inc. | NR4A-deficient cells expressing c-Jun and uses thereof |
KR20240055811A (ko) | 2021-09-10 | 2024-04-29 | 애질런트 테크놀로지스, 인크. | 프라임 편집을 위한 화학적 변형을 갖는 가이드 rna |
CN118119702A (zh) | 2021-10-14 | 2024-05-31 | 隆萨销售股份有限公司 | 用于细胞外囊泡产生的经修饰的生产者细胞 |
WO2023077053A2 (en) | 2021-10-28 | 2023-05-04 | Regeneron Pharmaceuticals, Inc. | Crispr/cas-related methods and compositions for knocking out c5 |
WO2023077148A1 (en) | 2021-11-01 | 2023-05-04 | Tome Biosciences, Inc. | Single construct platform for simultaneous delivery of gene editing machinery and nucleic acid cargo |
AU2022381205A1 (en) | 2021-11-04 | 2024-03-28 | Regeneron Pharmaceuticals, Inc. | Non-human animals comprising a modified cacng1 locus |
AU2022408167A1 (en) | 2021-12-08 | 2024-06-06 | Regeneron Pharmaceuticals, Inc. | Mutant myocilin disease model and uses thereof |
GB202118058D0 (en) | 2021-12-14 | 2022-01-26 | Univ Warwick | Methods to increase yields in crops |
US20230279442A1 (en) | 2021-12-15 | 2023-09-07 | Versitech Limited | Engineered cas9-nucleases and method of use thereof |
WO2023122506A1 (en) | 2021-12-20 | 2023-06-29 | Regeneron Pharmaceuticals, Inc. | Non-human animals comprising humanized ace2 and tmprss loci |
WO2023122764A1 (en) | 2021-12-22 | 2023-06-29 | Tome Biosciences, Inc. | Co-delivery of a gene editor construct and a donor template |
AU2022424002A1 (en) | 2021-12-29 | 2024-06-13 | Bristol-Myers Squibb Company | Generation of landing pad cell lines |
WO2023150181A1 (en) | 2022-02-01 | 2023-08-10 | President And Fellows Of Harvard College | Methods and compositions for treating cancer |
WO2023150620A1 (en) | 2022-02-02 | 2023-08-10 | Regeneron Pharmaceuticals, Inc. | Crispr-mediated transgene insertion in neonatal cells |
WO2023150798A1 (en) | 2022-02-07 | 2023-08-10 | Regeneron Pharmaceuticals, Inc. | Compositions and methods for defining optimal treatment timeframes in lysosomal disease |
WO2023205744A1 (en) | 2022-04-20 | 2023-10-26 | Tome Biosciences, Inc. | Programmable gene insertion compositions |
WO2023212677A2 (en) | 2022-04-29 | 2023-11-02 | Regeneron Pharmaceuticals, Inc. | Identification of tissue-specific extragenic safe harbors for gene therapy approaches |
WO2023215831A1 (en) | 2022-05-04 | 2023-11-09 | Tome Biosciences, Inc. | Guide rna compositions for programmable gene insertion |
WO2023220603A1 (en) | 2022-05-09 | 2023-11-16 | Regeneron Pharmaceuticals, Inc. | Vectors and methods for in vivo antibody production |
WO2023225665A1 (en) | 2022-05-19 | 2023-11-23 | Lyell Immunopharma, Inc. | Polynucleotides targeting nr4a3 and uses thereof |
WO2023225670A2 (en) | 2022-05-20 | 2023-11-23 | Tome Biosciences, Inc. | Ex vivo programmable gene insertion |
WO2023235726A2 (en) | 2022-05-31 | 2023-12-07 | Regeneron Pharmaceuticals, Inc. | Crispr interference therapeutics for c9orf72 repeat expansion disease |
WO2023235725A2 (en) | 2022-05-31 | 2023-12-07 | Regeneron Pharmaceuticals, Inc. | Crispr-based therapeutics for c9orf72 repeat expansion disease |
WO2023250384A2 (en) * | 2022-06-22 | 2023-12-28 | The Regents Of The University Of California | Crispr-cas effector polypeptides and methods of use thereof |
GB2621813A (en) | 2022-06-30 | 2024-02-28 | Univ Newcastle | Preventing disease recurrence in Mitochondrial replacement therapy |
WO2024020587A2 (en) | 2022-07-22 | 2024-01-25 | Tome Biosciences, Inc. | Pleiopluripotent stem cell programmable gene insertion |
WO2024026474A1 (en) | 2022-07-29 | 2024-02-01 | Regeneron Pharmaceuticals, Inc. | Compositions and methods for transferrin receptor (tfr)-mediated delivery to the brain and muscle |
WO2024026488A2 (en) | 2022-07-29 | 2024-02-01 | Regeneron Pharmaceuticals, Inc. | Non-human animals comprising a modified transferrin receptor locus |
WO2024031053A1 (en) | 2022-08-05 | 2024-02-08 | Regeneron Pharmaceuticals, Inc. | Aggregation-resistant variants of tdp-43 |
WO2024064958A1 (en) | 2022-09-23 | 2024-03-28 | Lyell Immunopharma, Inc. | Methods for culturing nr4a-deficient cells |
WO2024064952A1 (en) | 2022-09-23 | 2024-03-28 | Lyell Immunopharma, Inc. | Methods for culturing nr4a-deficient cells overexpressing c-jun |
WO2024073606A1 (en) | 2022-09-28 | 2024-04-04 | Regeneron Pharmaceuticals, Inc. | Antibody resistant modified receptors to enhance cell-based therapies |
WO2024077174A1 (en) | 2022-10-05 | 2024-04-11 | Lyell Immunopharma, Inc. | Methods for culturing nr4a-deficient cells |
WO2024083579A1 (en) | 2022-10-20 | 2024-04-25 | Basf Se | Regulatory nucleic acid molecules for enhancing gene expression in plants |
US20240182561A1 (en) | 2022-11-04 | 2024-06-06 | Regeneron Pharmaceuticals, Inc. | Calcium voltage-gated channel auxiliary subunit gamma 1 (cacng1) binding proteins and cacng1-mediated delivery to skeletal muscle |
US20240173426A1 (en) | 2022-11-14 | 2024-05-30 | Regeneron Pharmaceuticals, Inc. | Compositions and methods for fibroblast growth factor receptor 3-mediated delivery to astrocytes |
WO2024107670A1 (en) | 2022-11-16 | 2024-05-23 | Regeneron Pharmaceuticals, Inc. | Chimeric proteins comprising membrane bound il-12 with protease cleavable linkers |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007501626A (ja) * | 2003-08-08 | 2007-02-01 | サンガモ バイオサイエンシズ インコーポレイテッド | 標的化された切断及び組換えの方法及び組成物 |
JP2008525029A (ja) * | 2004-12-22 | 2008-07-17 | ニュークレオニクス・インコーポレイテッド | 遺伝子サイレンシングに有用なhbvおよびhcv保存配列 |
JP2009515874A (ja) * | 2005-11-11 | 2009-04-16 | コリア リサーチ インスティテュート オブ バイオサイエンス アンド バイオテクノロジー | E2epfucp−vhl相互作用及びその用途 |
JP2009528070A (ja) * | 2006-03-02 | 2009-08-06 | ザ オハイオ ステイト ユニバーシティ | 膵臓癌に関連するマイクロrna発現プロファイル |
WO2011146121A1 (en) * | 2010-05-17 | 2011-11-24 | Sangamo Biosciences, Inc. | Novel dna-binding proteins and uses thereof |
WO2011159369A1 (en) * | 2010-06-14 | 2011-12-22 | Iowa State University Research Foundation, Inc. | Nuclease activity of tal effector and foki fusion protein |
Family Cites Families (162)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4952496A (en) | 1984-03-30 | 1990-08-28 | Associated Universities, Inc. | Cloning and expression of the gene for bacteriophage T7 RNA polymerase |
WO1988008450A1 (en) | 1987-05-01 | 1988-11-03 | Birdwell Finlayson | Gene therapy for metabolite disorders |
US5350689A (en) | 1987-05-20 | 1994-09-27 | Ciba-Geigy Corporation | Zea mays plants and transgenic Zea mays plants regenerated from protoplasts or protoplast-derived cells |
US5767367A (en) | 1990-06-23 | 1998-06-16 | Hoechst Aktiengesellschaft | Zea mays (L.) with capability of long term, highly efficient plant regeneration including fertile transgenic maize plants having a heterologous gene, and their preparation |
US7150982B2 (en) | 1991-09-09 | 2006-12-19 | Third Wave Technologies, Inc. | RNA detection assays |
FR2763797B1 (fr) * | 1997-05-30 | 1999-07-16 | Tabacs & Allumettes Ind | Cigarette a tres faible taux de goudron presentant un gout de tabac comparable a celui d'une cigarette classique a plus fort taux de goudron |
US20040186071A1 (en) | 1998-04-13 | 2004-09-23 | Bennett C. Frank | Antisense modulation of CD40 expression |
US20020182673A1 (en) | 1998-05-15 | 2002-12-05 | Genentech, Inc. | IL-17 homologous polypedies and therapeutic uses thereof |
CA2361191A1 (en) | 1999-02-03 | 2000-08-10 | The Children's Medical Center Corporation | Gene repair involving the induction of double-stranded dna cleavage at a chromosomal target site |
US8183339B1 (en) * | 1999-10-12 | 2012-05-22 | Xigen S.A. | Cell-permeable peptide inhibitors of the JNK signal transduction pathway |
WO2002026967A2 (en) | 2000-09-25 | 2002-04-04 | Thomas Jefferson University | Targeted gene correction by single-stranded oligodeoxynucleotides |
JP4254931B1 (ja) | 2000-10-27 | 2009-04-15 | カイロン ソチエタ ア レスポンサビリタ リミタータ | A群連鎖球菌およびb群連鎖球菌由来の核酸およびタンパク質 |
US7033744B2 (en) * | 2001-03-16 | 2006-04-25 | Naoya Kobayashi | Method for proliferating a liver cell, a liver cell obtained thereby, and use thereof |
IL159756A0 (en) | 2001-07-12 | 2004-06-20 | Univ Massachusetts | IN VIVO PRODUCTION OF SMALL INTERFERING RNAs THAT MEDIATE GENE SILENCING |
US20060253913A1 (en) | 2001-12-21 | 2006-11-09 | Yue-Jin Huang | Production of hSA-linked butyrylcholinesterases in transgenic mammals |
BR0307383A (pt) | 2002-01-23 | 2005-04-26 | Univ Utah Res Found | Mutagênese cromossomica alvo utilizando nucleases de ramificações de zinco |
WO2003080809A2 (en) | 2002-03-21 | 2003-10-02 | Sangamo Biosciences, Inc. | Methods and compositions for using zinc finger endonucleases to enhance homologous recombination |
AU2003224897A1 (en) | 2002-04-09 | 2003-10-27 | Kenneth L. Beattie | Oligonucleotide probes for genosensor chips |
AU2003233719A1 (en) * | 2002-06-06 | 2003-12-22 | Her Majesty The Queen In Right Of Canada As Represented By The Minister Of Agriculture And Agri-Food | Modifying the dna recombination potential in eukaryotes |
JP2006502748A (ja) | 2002-09-05 | 2006-01-26 | カリフォルニア インスティテュート オブ テクノロジー | 遺伝子ターゲッティングを誘発するキメラヌクレアーゼの使用方法 |
DE10260805A1 (de) * | 2002-12-23 | 2004-07-22 | Geneart Gmbh | Verfahren und Vorrichtung zum Optimieren einer Nucleotidsequenz zur Expression eines Proteins |
US8053232B2 (en) | 2004-01-23 | 2011-11-08 | Virxsys Corporation | Correction of alpha-1-antitrypsin genetic defects using spliceosome mediated RNA trans splicing |
US7972854B2 (en) | 2004-02-05 | 2011-07-05 | Sangamo Biosciences, Inc. | Methods and compositions for targeted cleavage and recombination |
US20050220796A1 (en) | 2004-03-31 | 2005-10-06 | Dynan William S | Compositions and methods for modulating DNA repair |
US7919277B2 (en) | 2004-04-28 | 2011-04-05 | Danisco A/S | Detection and typing of bacterial strains |
US7892224B2 (en) | 2005-06-01 | 2011-02-22 | Brainlab Ag | Inverse catheter planning |
US7534819B2 (en) | 2005-06-10 | 2009-05-19 | University Of Washington | Compositions and methods for intracellular delivery of biotinylated cargo |
US20060282289A1 (en) | 2005-06-14 | 2006-12-14 | Healthmatch Solutions, Llc | System and method for health care financing |
US20100055793A1 (en) * | 2005-07-25 | 2010-03-04 | Johns Hopkins University | Site-specific modification of the human genome using custom-designed zinc finger nucleases |
KR20080033455A (ko) | 2005-07-26 | 2008-04-16 | 상가모 바이오사이언스 인코포레이티드 | 외래 핵산 서열의 표적화된 통합 및 발현 |
US10022457B2 (en) | 2005-08-05 | 2018-07-17 | Gholam A. Peyman | Methods to regulate polarization and enhance function of cells |
NZ597299A (en) | 2005-08-26 | 2013-03-28 | Dupont Nutrition Biosci Aps | Use of a cas gene in combination with CRISPR repeats for modulating resistance in a cell |
US9677123B2 (en) | 2006-03-15 | 2017-06-13 | Siemens Healthcare Diagnostics Inc. | Degenerate nucleobase analogs |
WO2007126856A2 (en) * | 2006-03-28 | 2007-11-08 | Novartis Ag | Covalently-linked complexes of hiv tat and env proteins |
ATE513053T1 (de) | 2006-05-10 | 2011-07-15 | Deinove Sa | Verfahren zur chromosomenmanipulation unter verwendung eines neuen dna-reparatursystems |
US9399801B2 (en) | 2006-05-19 | 2016-07-26 | Dupont Nutrition Biosciences Aps | Tagged microorganisms and methods of tagging |
EP2019839B1 (en) | 2006-05-25 | 2011-12-07 | Sangamo BioSciences, Inc. | Methods and compositions for gene inactivation |
ES2610811T3 (es) | 2006-06-16 | 2017-05-03 | Dupont Nutrition Biosciences Aps | Bacteria Streptococcus thermophilus |
WO2008019123A2 (en) * | 2006-08-04 | 2008-02-14 | Georgia State University Research Foundation, Inc. | Enzyme sensors, methods for preparing and using such sensors, and methods of detecting protease activity |
MX2009009071A (es) | 2007-03-02 | 2009-09-24 | Danisco | Cultivos con resistencia mejorada a fagos. |
GB0806086D0 (en) | 2008-04-04 | 2008-05-14 | Ulive Entpr Ltd | Dendrimer polymer hybrids |
US8546553B2 (en) | 2008-07-25 | 2013-10-01 | University Of Georgia Research Foundation, Inc. | Prokaryotic RNAi-like system and methods of use |
AU2009283194B2 (en) | 2008-08-22 | 2014-10-16 | Sangamo Therapeutics, Inc. | Methods and compositions for targeted single-stranded cleavage and targeted integration |
DK2334794T3 (en) | 2008-09-15 | 2017-02-20 | Children's Medical Center Corp | MODULATION OF BCL11A FOR TREATMENT OF HEMOGLOBINOPATHIES |
US20100076057A1 (en) * | 2008-09-23 | 2010-03-25 | Northwestern University | TARGET DNA INTERFERENCE WITH crRNA |
US9404098B2 (en) | 2008-11-06 | 2016-08-02 | University Of Georgia Research Foundation, Inc. | Method for cleaving a target RNA using a Cas6 polypeptide |
DK2362915T3 (en) | 2008-11-07 | 2017-03-27 | Dupont Nutrition Biosci Aps | CRISPR SEQUENCES OF BIFIDOBACTERIA |
EP2789687A1 (en) | 2008-12-12 | 2014-10-15 | DuPont Nutrition Biosciences ApS | Genetic cluster of strains of Streptococcus thermophilus having unique rheological properties for dairy fermentation |
WO2010075424A2 (en) | 2008-12-22 | 2010-07-01 | The Regents Of University Of California | Compositions and methods for downregulating prokaryotic genes |
GB0823658D0 (en) | 2008-12-30 | 2009-02-04 | Angiomed Ag | Stent delivery device |
US8392349B2 (en) | 2009-02-23 | 2013-03-05 | Shalini Vajjhala | Global adaptation atlas and method of creating same |
AU2010235161B2 (en) | 2009-04-09 | 2015-01-22 | Sangamo Therapeutics, Inc. | Targeted integration into stem cells |
PT2424571T (pt) | 2009-04-30 | 2020-05-06 | Ospedale San Raffaele Srl | Vetor génico |
AU2010275432A1 (en) | 2009-07-24 | 2012-02-02 | Sigma-Aldrich Co. Llc. | Method for genome editing |
US20120192298A1 (en) * | 2009-07-24 | 2012-07-26 | Sigma Aldrich Co. Llc | Method for genome editing |
EP2727600B1 (en) | 2009-07-28 | 2019-03-27 | Sangamo Therapeutics, Inc. | Zinc finger fusion proteins for repressing a huntington gene |
KR101418355B1 (ko) | 2009-10-23 | 2014-07-11 | (주)바이오니아 | 고밀도 유전자 합성기 |
DE102009052674B4 (de) | 2009-11-12 | 2012-10-18 | Karl Weinhold | Verfahren und Vorrichtung zum Verbinden von Doppelmantelrohren |
US20110294114A1 (en) | 2009-12-04 | 2011-12-01 | Cincinnati Children's Hospital Medical Center | Optimization of determinants for successful genetic correction of diseases, mediated by hematopoietic stem cells |
DK2816112T3 (en) | 2009-12-10 | 2018-11-19 | Univ Minnesota | TAL effector-mediated DNA modification |
EP2534163B1 (en) | 2010-02-09 | 2015-11-04 | Sangamo BioSciences, Inc. | Targeted genomic modification with partially single-stranded donor molecules |
US10087431B2 (en) | 2010-03-10 | 2018-10-02 | The Regents Of The University Of California | Methods of generating nucleic acid fragments |
JP5926242B2 (ja) | 2010-05-10 | 2016-05-25 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | エンドリボヌクレアーゼ組成物およびその使用方法 |
US20140148361A1 (en) | 2010-06-07 | 2014-05-29 | Barry L. Stoddard | Generation and Expression of Engineered I-ONUI Endonuclease and Its Homologues and Uses Thereof |
EP2392208B1 (en) * | 2010-06-07 | 2016-05-04 | Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) | Fusion proteins comprising a DNA-binding domain of a Tal effector protein and a non-specific cleavage domain of a restriction nuclease and their use |
SG187075A1 (en) * | 2010-07-23 | 2013-03-28 | Sigma Aldrich Co Llc | Genome editing using targeting endonucleases and single-stranded nucleic acids |
US9081737B2 (en) | 2010-08-02 | 2015-07-14 | Integrated Dna Technologies, Inc. | Methods for predicting stability and melting temperatures of nucleic acid duplexes |
DK2630156T3 (en) | 2010-10-20 | 2018-12-17 | Dupont Nutrition Biosci Aps | CRISPR-CAS SEQUENCES OF LACTOCOCCUS |
WO2012069657A1 (en) * | 2010-11-26 | 2012-05-31 | Institut Pasteur | Identification of a human gyrovirus and applications. |
WO2012087756A1 (en) | 2010-12-22 | 2012-06-28 | Sangamo Biosciences, Inc. | Zinc finger nuclease modification of leucine rich repeat kinase 2 (lrrk2) mutant fibroblasts and ipscs |
KR20120096395A (ko) | 2011-02-22 | 2012-08-30 | 주식회사 툴젠 | 뉴클레아제에 의해 유전자 변형된 세포를 농축시키는 방법 |
WO2012164565A1 (en) | 2011-06-01 | 2012-12-06 | Yeda Research And Development Co. Ltd. | Compositions and methods for downregulating prokaryotic genes |
IL277027B (en) | 2011-09-21 | 2022-07-01 | Sangamo Therapeutics Inc | Methods and preparations for regulating transgene expression |
JP6144691B2 (ja) * | 2011-11-16 | 2017-06-07 | サンガモ セラピューティクス, インコーポレイテッド | 修飾されたdna結合タンパク質およびその使用 |
US8450107B1 (en) | 2011-11-30 | 2013-05-28 | The Broad Institute Inc. | Nucleotide-specific recognition sequences for designer TAL effectors |
GB201122458D0 (en) | 2011-12-30 | 2012-02-08 | Univ Wageningen | Modified cascade ribonucleoproteins and uses thereof |
SG10201606959PA (en) | 2012-02-24 | 2016-09-29 | Hutchinson Fred Cancer Res | Compositions and methods for the treatment of hemoglobinopathies |
CA2865011C (en) | 2012-02-29 | 2021-06-15 | Sangamo Biosciences, Inc. | Methods and compositions for treating huntington's disease |
US9637739B2 (en) | 2012-03-20 | 2017-05-02 | Vilnius University | RNA-directed DNA cleavage by the Cas9-crRNA complex |
WO2013141680A1 (en) | 2012-03-20 | 2013-09-26 | Vilnius University | RNA-DIRECTED DNA CLEAVAGE BY THE Cas9-crRNA COMPLEX |
AU2013204327B2 (en) | 2012-04-20 | 2016-09-01 | Aviagen | Cell transfection method |
CN104245940A (zh) | 2012-04-23 | 2014-12-24 | 拜尔作物科学公司 | 植物中的靶向基因组工程 |
IN2014DN09261A (ja) | 2012-04-25 | 2015-07-10 | Regeneron Pharma | |
BR112014027227B1 (pt) | 2012-05-02 | 2022-04-19 | Sangamo Biosciences, Inc. | Métodos para produzir uma planta que apresenta expressão reduzida do gene endógeno de malato desidrogenase (mdh), e para aumentar o rendimento da cultura |
CN104471067B (zh) | 2012-05-07 | 2020-08-14 | 桑格摩生物治疗股份有限公司 | 用于核酸酶介导的转基因靶向整合的方法和组合物 |
US11120889B2 (en) | 2012-05-09 | 2021-09-14 | Georgia Tech Research Corporation | Method for synthesizing a nuclease with reduced off-site cleavage |
MA37663B1 (fr) * | 2012-05-25 | 2019-12-31 | Univ California | Procédés et compositions permettant la modification de l'adn cible dirigée par l'arn et la modulation de la transcription dirigée par l'arn |
MX2014014650A (es) | 2012-05-30 | 2015-10-14 | Univ Washington | Minivectores superenrollados como una herramienta para la reparacion, alteración y reemplazo de ácido desoxirribonucleico. |
WO2013188037A2 (en) | 2012-06-11 | 2013-12-19 | Agilent Technologies, Inc | Method of adaptor-dimer subtraction using a crispr cas6 protein |
MX2014015204A (es) | 2012-06-12 | 2015-08-07 | Genentech Inc | Metodos y composiciones para generar alelos con inactivacion condicional. |
EP2674501A1 (en) | 2012-06-14 | 2013-12-18 | Agence nationale de sécurité sanitaire de l'alimentation,de l'environnement et du travail | Method for detecting and identifying enterohemorrhagic Escherichia coli |
US9688971B2 (en) | 2012-06-15 | 2017-06-27 | The Regents Of The University Of California | Endoribonuclease and methods of use thereof |
EP2861737B1 (en) | 2012-06-19 | 2019-04-17 | Regents Of The University Of Minnesota | Gene targeting in plants using dna viruses |
JP6329537B2 (ja) | 2012-07-11 | 2018-05-23 | サンガモ セラピューティクス, インコーポレイテッド | 生物学的薬剤の送達のための方法および組成物 |
ES2813080T3 (es) | 2012-07-11 | 2021-03-22 | Sangamo Therapeutics Inc | Métodos y composiciones para el tratamiento de enfermedades por almacenamiento lisosomal |
CN116622704A (zh) | 2012-07-25 | 2023-08-22 | 布罗德研究所有限公司 | 可诱导的dna结合蛋白和基因组干扰工具及其应用 |
WO2014022702A2 (en) | 2012-08-03 | 2014-02-06 | The Regents Of The University Of California | Methods and compositions for controlling gene expression by rna processing |
EA039384B1 (ru) | 2012-08-29 | 2022-01-20 | Сангамо Байосаенсез, Инк. | Белок "цинковые пальцы" для модулирования экспрессии гена bcl11a и способ модулирования экспрессии глобинового гена |
UA119135C2 (uk) | 2012-09-07 | 2019-05-10 | ДАУ АГРОСАЙЄНСІЗ ЕлЕлСі | Спосіб отримання трансгенної рослини |
AU2013312538B2 (en) | 2012-09-07 | 2019-01-24 | Corteva Agriscience Llc | FAD3 performance loci and corresponding target site specific binding proteins capable of inducing targeted breaks |
UA118090C2 (uk) | 2012-09-07 | 2018-11-26 | ДАУ АГРОСАЙЄНСІЗ ЕлЕлСі | Спосіб інтегрування послідовності нуклеїнової кислоти, що представляє інтерес, у ген fad2 у клітині сої та специфічний для локусу fad2 білок, що зв'язується, здатний індукувати спрямований розрив |
US20150267176A1 (en) | 2012-10-12 | 2015-09-24 | The General Hospital Corporation | Transcription activator-like effector (tale) - lysine-specific demethylase 1 (lsd1) fusion proteins |
KR102182847B1 (ko) | 2012-10-23 | 2020-11-27 | 주식회사 툴젠 | 표적 DNA에 특이적인 가이드 RNA 및 Cas 단백질을 암호화하는 핵산 또는 Cas 단백질을 포함하는, 표적 DNA를 절단하기 위한 조성물 및 이의 용도 |
WO2014070887A1 (en) | 2012-10-30 | 2014-05-08 | Recombinetics, Inc. | Control of sexual maturation in animals |
WO2014071006A1 (en) | 2012-10-31 | 2014-05-08 | Cellectis | Coupling herbicide resistance with targeted insertion of transgenes in plants |
US20140127752A1 (en) | 2012-11-07 | 2014-05-08 | Zhaohui Zhou | Method, composition, and reagent kit for targeted genomic enrichment |
EP3617309A3 (en) | 2012-12-06 | 2020-05-06 | Sigma Aldrich Co. LLC | Crispr-based genome modification and regulation |
WO2014093479A1 (en) | 2012-12-11 | 2014-06-19 | Montana State University | Crispr (clustered regularly interspaced short palindromic repeats) rna-guided control of gene regulation |
KR20150105634A (ko) | 2012-12-12 | 2015-09-17 | 더 브로드 인스티튜트, 인코퍼레이티드 | 서열 조작을 위한 개선된 시스템, 방법 및 효소 조성물의 유전자 조작 및 최적화 |
US8697359B1 (en) | 2012-12-12 | 2014-04-15 | The Broad Institute, Inc. | CRISPR-Cas systems and methods for altering expression of gene products |
DK2931898T3 (en) * | 2012-12-12 | 2016-06-20 | Massachusetts Inst Technology | CONSTRUCTION AND OPTIMIZATION OF SYSTEMS, PROCEDURES AND COMPOSITIONS FOR SEQUENCE MANIPULATION WITH FUNCTIONAL DOMAINS |
WO2014093709A1 (en) | 2012-12-12 | 2014-06-19 | The Broad Institute, Inc. | Methods, models, systems, and apparatus for identifying target sequences for cas enzymes or crispr-cas systems for target sequences and conveying results thereof |
US20140310830A1 (en) | 2012-12-12 | 2014-10-16 | Feng Zhang | CRISPR-Cas Nickase Systems, Methods And Compositions For Sequence Manipulation in Eukaryotes |
IL293526A (en) | 2012-12-12 | 2022-08-01 | Harvard College | Providing, engineering and optimizing systems, methods and compositions for sequence manipulation and therapeutic applications |
PT2771468E (pt) | 2012-12-12 | 2015-06-02 | Harvard College | Engenharia de sistemas, métodos e composições-guia otimizadas para manipulação de sequências |
WO2014093595A1 (en) | 2012-12-12 | 2014-06-19 | The Broad Institute, Inc. | Crispr-cas component systems, methods and compositions for sequence manipulation |
EP3064585B1 (en) | 2012-12-12 | 2020-02-05 | The Broad Institute, Inc. | Engineering and optimization of improved systems, methods and enzyme compositions for sequence manipulation |
EP2931899A1 (en) | 2012-12-12 | 2015-10-21 | The Broad Institute, Inc. | Functional genomics using crispr-cas systems, compositions, methods, knock out libraries and applications thereof |
AR093979A1 (es) | 2012-12-13 | 2015-07-01 | Dow Agrosciences Llc | Metodos de deteccion de adn para actividad de nucleasa especifica de sitio |
ES2741951T3 (es) | 2012-12-17 | 2020-02-12 | Harvard College | Modificación por ingeniería genética del genoma humano guiada por ARN |
EP2938184B1 (en) | 2012-12-27 | 2018-10-31 | Keygene N.V. | Method for removing genetic linkage in a plant |
CN113005148A (zh) | 2013-01-16 | 2021-06-22 | 爱默蕾大学 | Cas9-核酸复合物及其相关用途 |
CN103233028B (zh) | 2013-01-25 | 2015-05-13 | 南京徇齐生物技术有限公司 | 一种无物种限制无生物安全性问题的真核生物基因打靶方法及螺旋结构dna序列 |
WO2014127287A1 (en) | 2013-02-14 | 2014-08-21 | Massachusetts Institute Of Technology | Method for in vivo tergated mutagenesis |
RU2690352C2 (ru) | 2013-02-20 | 2019-05-31 | Регенерон Фармасютикалс, Инк. | Генетическая модификация крыс |
AU2014218621B2 (en) | 2013-02-25 | 2019-11-07 | Sangamo Therapeutics, Inc. | Methods and compositions for enhancing nuclease-mediated gene disruption |
RU2018122288A (ru) | 2013-03-14 | 2019-03-06 | Карибо Биосайенсиз, Инк. | Композиции и способы с участием нуклеиновых кислот, нацеленных на нуклеиновые кислоты |
US9234213B2 (en) | 2013-03-15 | 2016-01-12 | System Biosciences, Llc | Compositions and methods directed to CRISPR/Cas genomic engineering systems |
US10760064B2 (en) | 2013-03-15 | 2020-09-01 | The General Hospital Corporation | RNA-guided targeting of genetic and epigenomic regulatory proteins to specific genomic loci |
AU2014227653B2 (en) | 2013-03-15 | 2017-04-20 | The General Hospital Corporation | Using RNA-guided foki nucleases (RFNs) to increase specificity for RNA-guided genome editing |
US11332719B2 (en) | 2013-03-15 | 2022-05-17 | The Broad Institute, Inc. | Recombinant virus and preparations thereof |
US20140364333A1 (en) | 2013-03-15 | 2014-12-11 | President And Fellows Of Harvard College | Methods for Live Imaging of Cells |
US20140273230A1 (en) | 2013-03-15 | 2014-09-18 | Sigma-Aldrich Co., Llc | Crispr-based genome modification and regulation |
US20140273235A1 (en) | 2013-03-15 | 2014-09-18 | Regents Of The University Of Minnesota | ENGINEERING PLANT GENOMES USING CRISPR/Cas SYSTEMS |
WO2014165825A2 (en) | 2013-04-04 | 2014-10-09 | President And Fellows Of Harvard College | Therapeutic uses of genome editing with crispr/cas systems |
CA2908512C (en) | 2013-04-05 | 2023-10-24 | Dow Agrosciences Llc | Methods and compositions for integration of an exogenous sequence within the genome of plants |
SI2986729T1 (sl) | 2013-04-16 | 2019-02-28 | Regeneron Pharmaceuticals, Inc. | Ciljana sprememba genoma podgane |
CN103224947B (zh) | 2013-04-28 | 2015-06-10 | 陕西师范大学 | 一种基因打靶*** |
CA2910427C (en) | 2013-05-10 | 2024-02-20 | Sangamo Biosciences, Inc. | Delivery methods and compositions for nuclease-mediated genome engineering |
EP2999788B1 (en) | 2013-05-22 | 2020-07-08 | Northwestern University | Rna-directed dna cleavage and gene editing by cas9 enzyme from neisseria meningitidis |
US11414695B2 (en) | 2013-05-29 | 2022-08-16 | Agilent Technologies, Inc. | Nucleic acid enrichment using Cas9 |
US20140356956A1 (en) | 2013-06-04 | 2014-12-04 | President And Fellows Of Harvard College | RNA-Guided Transcriptional Regulation |
ES2767318T3 (es) | 2013-06-17 | 2020-06-17 | Broad Inst Inc | Suministro, modificación y optimización de sistemas, métodos y composiciones para generar modelos y actuar sobre enfermedades y trastornos de células posmitóticas |
AU2014281027A1 (en) | 2013-06-17 | 2016-01-28 | Massachusetts Institute Of Technology | Optimized CRISPR-Cas double nickase systems, methods and compositions for sequence manipulation |
SG11201510284XA (en) | 2013-06-17 | 2016-01-28 | Broad Inst Inc | Delivery and use of the crispr-cas systems, vectors and compositions for hepatic targeting and therapy |
EP3011034B1 (en) | 2013-06-17 | 2019-08-07 | The Broad Institute, Inc. | Delivery, use and therapeutic applications of the crispr-cas systems and compositions for targeting disorders and diseases using viral components |
EP3725885A1 (en) | 2013-06-17 | 2020-10-21 | The Broad Institute, Inc. | Functional genomics using crispr-cas systems, compositions methods, screens and applications thereof |
CN103343120B (zh) | 2013-07-04 | 2015-03-04 | 中国科学院遗传与发育生物学研究所 | 一种小麦基因组定点改造方法 |
CN103382468B (zh) * | 2013-07-04 | 2015-04-29 | 中国科学院遗传与发育生物学研究所 | 一种水稻基因组定点改造方法 |
IL282489B (en) | 2013-07-10 | 2022-07-01 | Harvard College | Cas9 proteins are orthogonal to the regulation and editing of guided genes - RNA |
CN103388006B (zh) | 2013-07-26 | 2015-10-28 | 华东师范大学 | 一种基因定点突变的构建方法 |
US10421957B2 (en) | 2013-07-29 | 2019-09-24 | Agilent Technologies, Inc. | DNA assembly using an RNA-programmable nickase |
EP3065540B1 (en) | 2013-11-04 | 2021-12-15 | Corteva Agriscience LLC | Optimal maize loci |
MX362066B (es) | 2013-11-04 | 2019-01-07 | Dow Agrosciences Llc | Loci óptimos de soya. |
TWI672378B (zh) | 2013-11-04 | 2019-09-21 | 陶氏農業科學公司 | 最適大豆基因座(一) |
CN106459995B (zh) | 2013-11-07 | 2020-02-21 | 爱迪塔斯医药有限公司 | 使用统治型gRNA的CRISPR相关方法和组合物 |
MX2016007654A (es) | 2013-12-11 | 2017-08-15 | Regeneron Pharma | Metodos y composiciones para la modificacion dirigida de un genoma. |
US9850525B2 (en) | 2014-01-29 | 2017-12-26 | Agilent Technologies, Inc. | CAS9-based isothermal method of detection of specific DNA sequence |
WO2015117041A1 (en) | 2014-01-30 | 2015-08-06 | Nair Ramesh B | Gene modification-mediated methods and compositions for generating dominant traits in eukaryotic systems |
US20150225801A1 (en) | 2014-02-11 | 2015-08-13 | California Institute Of Technology | Recording and mapping lineage information and molecular events in individual cells |
EP3110454B1 (en) | 2014-02-24 | 2020-11-18 | Sangamo Therapeutics, Inc. | Methods and compositions for nuclease-mediated targeted integration |
US9624498B2 (en) | 2014-03-18 | 2017-04-18 | Sangamo Biosciences, Inc. | Methods and compositions for regulation of zinc finger protein expression |
-
2013
- 2013-12-05 EP EP19189913.7A patent/EP3617309A3/en active Pending
- 2013-12-05 ES ES16183725T patent/ES2713243T3/es active Active
- 2013-12-05 SG SG10201800585VA patent/SG10201800585VA/en unknown
- 2013-12-05 EP EP16183720.8A patent/EP3141604A1/en not_active Withdrawn
- 2013-12-05 US US14/649,777 patent/US20160017366A1/en not_active Abandoned
- 2013-12-05 PT PT16183725T patent/PT3138912T/pt unknown
- 2013-12-05 ES ES16183724T patent/ES2714154T3/es active Active
- 2013-12-05 EP EP13859964.2A patent/EP2928496B1/en not_active Revoked
- 2013-12-05 ES ES18160519T patent/ES2769310T3/es active Active
- 2013-12-05 CA CA2977152A patent/CA2977152C/en active Active
- 2013-12-05 ES ES18156734T patent/ES2757808T3/es active Active
- 2013-12-05 DK DK18160519.7T patent/DK3363902T3/da active
- 2013-12-05 LT LTEP16183725.7T patent/LT3138912T/lt unknown
- 2013-12-05 BR BR112015012375A patent/BR112015012375A2/pt active Search and Examination
- 2013-12-05 PL PL13859964T patent/PL2928496T3/pl unknown
- 2013-12-05 DK DK16183724.0T patent/DK3138911T3/en active
- 2013-12-05 CA CA2891347A patent/CA2891347C/en active Active
- 2013-12-05 AU AU2013355214A patent/AU2013355214B2/en active Active
- 2013-12-05 PL PL16183723T patent/PL3138910T3/pl unknown
- 2013-12-05 LT LTEP18160519.7T patent/LT3363902T/lt unknown
- 2013-12-05 EP EP18156734.8A patent/EP3360964B1/en active Active
- 2013-12-05 CN CN201810540449.5A patent/CN108715602A/zh active Pending
- 2013-12-05 LT LTEP16183723.2T patent/LT3138910T/lt unknown
- 2013-12-05 EP EP16183725.7A patent/EP3138912B1/en not_active Revoked
- 2013-12-05 PL PL18156734T patent/PL3360964T3/pl unknown
- 2013-12-05 WO PCT/US2013/073307 patent/WO2014089290A1/en active Application Filing
- 2013-12-05 DK DK13859964T patent/DK2928496T3/da active
- 2013-12-05 PT PT181605197T patent/PT3363902T/pt unknown
- 2013-12-05 EP EP16183723.2A patent/EP3138910B1/en not_active Revoked
- 2013-12-05 EP EP16183717.4A patent/EP3138909A1/en not_active Withdrawn
- 2013-12-05 DK DK18156734T patent/DK3360964T3/da active
- 2013-12-05 PT PT138599642T patent/PT2928496T/pt unknown
- 2013-12-05 EP EP19201769.7A patent/EP3611263A1/en active Pending
- 2013-12-05 KR KR1020157013843A patent/KR101844123B1/ko active IP Right Review Request
- 2013-12-05 EP EP18160519.7A patent/EP3363902B1/en active Active
- 2013-12-05 KR KR1020187001934A patent/KR102006880B1/ko active IP Right Grant
- 2013-12-05 PT PT181567348T patent/PT3360964T/pt unknown
- 2013-12-05 IL IL300199A patent/IL300199A/en unknown
- 2013-12-05 ES ES13859964T patent/ES2757325T3/es active Active
- 2013-12-05 EP EP16183719.0A patent/EP3135765A1/en not_active Withdrawn
- 2013-12-05 DK DK16183725.7T patent/DK3138912T3/en active
- 2013-12-05 PL PL18160519T patent/PL3363902T3/pl unknown
- 2013-12-05 CN CN201810574719.4A patent/CN108913676B/zh active Active
- 2013-12-05 DK DK16183723.2T patent/DK3138910T3/en active
- 2013-12-05 PT PT16183724T patent/PT3138911T/pt unknown
- 2013-12-05 SG SG10202107423UA patent/SG10202107423UA/en unknown
- 2013-12-05 ES ES16183723.2T patent/ES2653212T3/es active Active
- 2013-12-05 SG SG10201910987SA patent/SG10201910987SA/en unknown
- 2013-12-05 EP EP16183724.0A patent/EP3138911B1/en active Active
- 2013-12-05 JP JP2015545838A patent/JP6620018B2/ja active Active
- 2013-12-05 CN CN201380072477.4A patent/CN105142669B/zh active Active
- 2013-12-05 PL PL16183724T patent/PL3138911T3/pl unknown
- 2013-12-05 LT LTEP16183724.0T patent/LT3138911T/lt unknown
- 2013-12-05 KR KR1020217011309A patent/KR102479178B1/ko active IP Right Grant
- 2013-12-05 PL PL16183725T patent/PL3138912T3/pl unknown
- 2013-12-05 SG SG11201503824SA patent/SG11201503824SA/en unknown
- 2013-12-05 KR KR1020197022305A patent/KR102145760B1/ko active IP Right Grant
- 2013-12-05 KR KR1020207023229A patent/KR102243092B1/ko active IP Right Grant
- 2013-12-05 CA CA3034794A patent/CA3034794A1/en active Pending
- 2013-12-05 PT PT161837232T patent/PT3138910T/pt unknown
- 2013-12-05 KR KR1020227043854A patent/KR102531576B1/ko active IP Right Grant
-
2015
- 2015-05-17 IL IL238856A patent/IL238856B/en active IP Right Grant
-
2016
- 2016-06-06 HK HK16106396.9A patent/HK1218389A1/zh unknown
- 2016-06-21 US US15/188,909 patent/US20160298133A1/en not_active Abandoned
- 2016-06-21 US US15/188,933 patent/US20160298138A1/en not_active Abandoned
- 2016-06-21 US US15/188,927 patent/US20160298136A1/en not_active Abandoned
- 2016-06-21 US US15/188,924 patent/US10745716B2/en active Active
- 2016-06-21 US US15/188,899 patent/US20160298125A1/en not_active Abandoned
- 2016-06-21 US US15/188,931 patent/US20160298137A1/en not_active Abandoned
- 2016-06-21 US US15/188,911 patent/US10731181B2/en active Active
- 2016-06-21 US US15/188,902 patent/US20160298132A1/en not_active Abandoned
- 2016-11-03 US US15/342,976 patent/US20170073705A1/en not_active Abandoned
-
2017
- 2017-03-10 US US15/456,204 patent/US20170191082A1/en active Pending
- 2017-06-13 JP JP2017115672A patent/JP2017192392A/ja active Pending
- 2017-06-15 AU AU2017204031A patent/AU2017204031B2/en active Active
-
2018
- 2018-01-28 IL IL257178A patent/IL257178B/en active IP Right Grant
- 2018-09-13 AU AU2018229489A patent/AU2018229489B2/en active Active
- 2018-09-28 JP JP2018183815A patent/JP2019037231A/ja active Pending
-
2019
- 2019-02-26 AU AU2019201344A patent/AU2019201344C1/en active Active
- 2019-06-24 IL IL267598A patent/IL267598B/en unknown
- 2019-10-16 US US16/654,613 patent/US20200140897A1/en not_active Abandoned
-
2020
- 2020-04-17 JP JP2020074283A patent/JP2020120674A/ja active Pending
- 2020-07-30 US US16/943,792 patent/US20210079427A1/en not_active Abandoned
- 2020-07-30 US US16/943,767 patent/US20210207173A1/en active Pending
- 2020-09-08 AU AU2020230246A patent/AU2020230246B2/en active Active
- 2020-09-08 AU AU2020230243A patent/AU2020230243B2/en active Active
- 2020-11-19 AU AU2020273316A patent/AU2020273316B2/en active Active
-
2021
- 2021-03-03 JP JP2021033258A patent/JP2021101706A/ja active Pending
- 2021-08-10 US US17/398,648 patent/US20210388396A1/en active Pending
-
2022
- 2022-01-19 AU AU2022200330A patent/AU2022200330B2/en active Active
- 2022-03-06 IL IL291129A patent/IL291129B2/en unknown
- 2022-05-06 JP JP2022076698A patent/JP7478772B2/ja active Active
-
2023
- 2023-08-17 AU AU2023216829A patent/AU2023216829A1/en active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007501626A (ja) * | 2003-08-08 | 2007-02-01 | サンガモ バイオサイエンシズ インコーポレイテッド | 標的化された切断及び組換えの方法及び組成物 |
JP2008525029A (ja) * | 2004-12-22 | 2008-07-17 | ニュークレオニクス・インコーポレイテッド | 遺伝子サイレンシングに有用なhbvおよびhcv保存配列 |
JP2009515874A (ja) * | 2005-11-11 | 2009-04-16 | コリア リサーチ インスティテュート オブ バイオサイエンス アンド バイオテクノロジー | E2epfucp−vhl相互作用及びその用途 |
JP2009528070A (ja) * | 2006-03-02 | 2009-08-06 | ザ オハイオ ステイト ユニバーシティ | 膵臓癌に関連するマイクロrna発現プロファイル |
WO2011146121A1 (en) * | 2010-05-17 | 2011-11-24 | Sangamo Biosciences, Inc. | Novel dna-binding proteins and uses thereof |
WO2011159369A1 (en) * | 2010-06-14 | 2011-12-22 | Iowa State University Research Foundation, Inc. | Nuclease activity of tal effector and foki fusion protein |
Non-Patent Citations (13)
Title |
---|
ANNALS OF NEUROSCIENCES, 2011, VOL.18, P.25-28, JPN6016021648, ISSN: 0005082979 * |
BIORESEARCH OPEN ACCESS, JUN. 2012, VOL.1, P.99-108, JPN6017007679, ISSN: 0005082975 * |
GENE THER., vol. 15, JPN6021017510, 2008, pages 1463 - 1468, ISSN: 0005082968 * |
GENETICS, vol. 186, JPN6017012112, 2010, pages 757 - 761, ISSN: 0005082970 * |
METHODS, 2011, VOL.53, P.339-346, JPN6016021647, ISSN: 0005082977 * |
NATURE BIOTECHNOLOGY, vol. 29, no. 2, JPN6017012111, 2011, pages 143 - 148, ISSN: 0005082969 * |
NATURE METHODS, AUG. 2012, VOL.9, P.805-807, JPN6017007680, ISSN: 0005082976 * |
NUCLEIC ACIDS RESEARCH, 2011, VOL.40, P.3443-3455, JPN6016021650, ISSN: 0005082978 * |
NUCLEIC ACIDS RESEARCH, vol. Vol.39, e82, JPN6016021644, 2011, pages 1 - 11, ISSN: 0005082972 * |
PNAS, 2011, VOL.108, P.2623-2628, JPN6016021645, ISSN: 0005082973 * |
SCIENCE, 2003, VOL.300, P.763, JPN6017007678, ISSN: 0005082974 * |
SCIENCE, vol. 337, JPN6016021641, 2012, pages 816 - 821, ISSN: 0005082967 * |
ZEBRAFISH, 2011, VOL.8, P.147-149, JPN6016021642, ISSN: 0005082971 * |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7478772B2 (ja) | Crisprに基づくゲノム修飾および制御 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220603 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20220603 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220928 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230613 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20230912 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20231113 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20240116 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20240321 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20240409 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20240422 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7478772 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |