JP2023052079A - 免疫工学的な改変をした多能性細胞 - Google Patents
免疫工学的な改変をした多能性細胞 Download PDFInfo
- Publication number
- JP2023052079A JP2023052079A JP2022208126A JP2022208126A JP2023052079A JP 2023052079 A JP2023052079 A JP 2023052079A JP 2022208126 A JP2022208126 A JP 2022208126A JP 2022208126 A JP2022208126 A JP 2022208126A JP 2023052079 A JP2023052079 A JP 2023052079A
- Authority
- JP
- Japan
- Prior art keywords
- protein
- cells
- hla
- gene
- expression
- 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.)
- Pending
Links
- 239000000427 antigen Substances 0.000 claims abstract description 25
- 108091007433 antigens Proteins 0.000 claims abstract description 25
- 102000036639 antigens Human genes 0.000 claims abstract description 25
- 210000004027 cell Anatomy 0.000 claims description 571
- 108090000623 proteins and genes Proteins 0.000 claims description 191
- 230000014509 gene expression Effects 0.000 claims description 167
- 210000004263 induced pluripotent stem cell Anatomy 0.000 claims description 147
- 238000000034 method Methods 0.000 claims description 147
- 241000282414 Homo sapiens Species 0.000 claims description 86
- 230000002163 immunogen Effects 0.000 claims description 78
- 101150084532 CD47 gene Proteins 0.000 claims description 69
- 230000000735 allogeneic effect Effects 0.000 claims description 66
- 101000868279 Homo sapiens Leukocyte surface antigen CD47 Proteins 0.000 claims description 65
- 102100032913 Leukocyte surface antigen CD47 Human genes 0.000 claims description 65
- 230000003247 decreasing effect Effects 0.000 claims description 64
- 102000004169 proteins and genes Human genes 0.000 claims description 57
- 210000000822 natural killer cell Anatomy 0.000 claims description 50
- 101100382122 Homo sapiens CIITA gene Proteins 0.000 claims description 49
- 241000699666 Mus <mouse, genus> Species 0.000 claims description 47
- 210000000130 stem cell Anatomy 0.000 claims description 45
- 230000002829 reductive effect Effects 0.000 claims description 40
- 210000001778 pluripotent stem cell Anatomy 0.000 claims description 39
- 101150076800 B2M gene Proteins 0.000 claims description 38
- 102100027314 Beta-2-microglobulin Human genes 0.000 claims description 38
- 230000004048 modification Effects 0.000 claims description 38
- 238000012986 modification Methods 0.000 claims description 38
- 230000001965 increasing effect Effects 0.000 claims description 35
- 108700002010 MHC class II transactivator Proteins 0.000 claims description 34
- 108010081355 beta 2-Microglobulin Proteins 0.000 claims description 33
- 102100026371 MHC class II transactivator Human genes 0.000 claims description 31
- 102100037850 Interferon gamma Human genes 0.000 claims description 28
- 108010074328 Interferon-gamma Proteins 0.000 claims description 28
- 108700028369 Alleles Proteins 0.000 claims description 27
- 101100382123 Mus musculus Ciita gene Proteins 0.000 claims description 27
- 230000001939 inductive effect Effects 0.000 claims description 23
- 101000937544 Homo sapiens Beta-2-microglobulin Proteins 0.000 claims description 20
- 230000000694 effects Effects 0.000 claims description 20
- 108091033409 CRISPR Proteins 0.000 claims description 17
- 108010076667 Caspases Proteins 0.000 claims description 17
- 102000011727 Caspases Human genes 0.000 claims description 17
- 108700019146 Transgenes Proteins 0.000 claims description 17
- 230000036755 cellular response Effects 0.000 claims description 15
- 108010058597 HLA-DR Antigens Proteins 0.000 claims description 14
- 102000006354 HLA-DR Antigens Human genes 0.000 claims description 14
- 102100028972 HLA class I histocompatibility antigen, A alpha chain Human genes 0.000 claims description 13
- 108010075704 HLA-A Antigens Proteins 0.000 claims description 13
- 238000003114 enzyme-linked immunosorbent spot assay Methods 0.000 claims description 12
- 230000002147 killing effect Effects 0.000 claims description 12
- 102100028976 HLA class I histocompatibility antigen, B alpha chain Human genes 0.000 claims description 11
- 102100028971 HLA class I histocompatibility antigen, C alpha chain Human genes 0.000 claims description 11
- 108010058607 HLA-B Antigens Proteins 0.000 claims description 11
- 108010052199 HLA-C Antigens Proteins 0.000 claims description 11
- 108010010378 HLA-DP Antigens Proteins 0.000 claims description 11
- 102000015789 HLA-DP Antigens Human genes 0.000 claims description 11
- 108010062347 HLA-DQ Antigens Proteins 0.000 claims description 11
- 230000005867 T cell response Effects 0.000 claims description 11
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical group NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 claims description 10
- 229960004413 flucytosine Drugs 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 101150071002 Ciita gene Proteins 0.000 claims description 8
- 206010057249 Phagocytosis Diseases 0.000 claims description 8
- 210000002540 macrophage Anatomy 0.000 claims description 8
- 230000008782 phagocytosis Effects 0.000 claims description 8
- 238000011510 Elispot assay Methods 0.000 claims description 7
- 238000011577 humanized mouse model Methods 0.000 claims description 7
- 241000588724 Escherichia coli Species 0.000 claims description 6
- 108020004440 Thymidine kinase Proteins 0.000 claims description 6
- 230000004075 alteration Effects 0.000 claims description 6
- 238000006471 dimerization reaction Methods 0.000 claims description 6
- 238000000338 in vitro Methods 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 108010080611 Cytosine Deaminase Proteins 0.000 claims description 5
- 241000700584 Simplexvirus Species 0.000 claims description 5
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical group O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 claims description 5
- 229960002963 ganciclovir Drugs 0.000 claims description 5
- 239000000411 inducer Substances 0.000 claims description 5
- 210000004988 splenocyte Anatomy 0.000 claims description 4
- 101100059528 Mus musculus Cd47 gene Proteins 0.000 claims description 3
- 101100059527 Homo sapiens CD47 gene Proteins 0.000 claims description 2
- 102000015736 beta 2-Microglobulin Human genes 0.000 claims 11
- 101100338884 Mus musculus Hhip gene Proteins 0.000 claims 7
- 230000003472 neutralizing effect Effects 0.000 claims 1
- 230000028993 immune response Effects 0.000 abstract description 28
- 210000000056 organ Anatomy 0.000 abstract description 10
- 230000001172 regenerating effect Effects 0.000 abstract description 9
- 230000000242 pagocytic effect Effects 0.000 abstract description 2
- 230000012202 endocytosis Effects 0.000 abstract 1
- 239000002609 medium Substances 0.000 description 50
- 241000699670 Mus sp. Species 0.000 description 47
- 230000004069 differentiation Effects 0.000 description 45
- 108090000765 processed proteins & peptides Proteins 0.000 description 45
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 44
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 44
- 230000006870 function Effects 0.000 description 42
- 102000004196 processed proteins & peptides Human genes 0.000 description 42
- 229920001184 polypeptide Polymers 0.000 description 41
- 239000013598 vector Substances 0.000 description 35
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 30
- 238000011740 C57BL/6 mouse Methods 0.000 description 28
- 238000005516 engineering process Methods 0.000 description 28
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 27
- 102100035423 POU domain, class 5, transcription factor 1 Human genes 0.000 description 27
- 230000008672 reprogramming Effects 0.000 description 26
- 210000002889 endothelial cell Anatomy 0.000 description 25
- 238000002054 transplantation Methods 0.000 description 25
- 210000004413 cardiac myocyte Anatomy 0.000 description 24
- 101710126211 POU domain, class 5, transcription factor 1 Proteins 0.000 description 23
- 206010043276 Teratoma Diseases 0.000 description 23
- 238000003556 assay Methods 0.000 description 21
- 150000007523 nucleic acids Chemical group 0.000 description 20
- 230000001105 regulatory effect Effects 0.000 description 19
- 210000001519 tissue Anatomy 0.000 description 19
- 241001465754 Metazoa Species 0.000 description 17
- 108010010803 Gelatin Proteins 0.000 description 16
- 239000008273 gelatin Substances 0.000 description 16
- 229920000159 gelatin Polymers 0.000 description 16
- 235000019322 gelatine Nutrition 0.000 description 16
- 235000011852 gelatine desserts Nutrition 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 108020004414 DNA Proteins 0.000 description 15
- 102000004877 Insulin Human genes 0.000 description 15
- 108090001061 Insulin Proteins 0.000 description 15
- 101100247004 Rattus norvegicus Qsox1 gene Proteins 0.000 description 15
- 229940125396 insulin Drugs 0.000 description 15
- 108010082117 matrigel Proteins 0.000 description 15
- 230000004083 survival effect Effects 0.000 description 15
- 108091026890 Coding region Proteins 0.000 description 13
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 13
- 150000001413 amino acids Chemical class 0.000 description 13
- 210000002950 fibroblast Anatomy 0.000 description 13
- 238000004458 analytical method Methods 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 12
- 238000003776 cleavage reaction Methods 0.000 description 12
- 238000001514 detection method Methods 0.000 description 12
- 230000007017 scission Effects 0.000 description 12
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 11
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 11
- 229930189065 blasticidin Natural products 0.000 description 11
- 238000000684 flow cytometry Methods 0.000 description 11
- 230000004044 response Effects 0.000 description 11
- 238000003757 reverse transcription PCR Methods 0.000 description 11
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 11
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 10
- 241000282412 Homo Species 0.000 description 10
- 101000676246 Homo sapiens 60S ribosomal protein L29 Proteins 0.000 description 10
- 101001021500 Homo sapiens Hedgehog-interacting protein Proteins 0.000 description 10
- 101000687905 Homo sapiens Transcription factor SOX-2 Proteins 0.000 description 10
- 241000713666 Lentivirus Species 0.000 description 10
- 108091028043 Nucleic acid sequence Proteins 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 102100024270 Transcription factor SOX-2 Human genes 0.000 description 10
- 210000001900 endoderm Anatomy 0.000 description 10
- 239000012091 fetal bovine serum Substances 0.000 description 10
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 10
- -1 hTERT Proteins 0.000 description 10
- 102000046159 human RPL29 Human genes 0.000 description 10
- 238000010166 immunofluorescence Methods 0.000 description 10
- 102000039446 nucleic acids Human genes 0.000 description 10
- 108020004707 nucleic acids Proteins 0.000 description 10
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 10
- 101001139134 Homo sapiens Krueppel-like factor 4 Proteins 0.000 description 9
- 108060003951 Immunoglobulin Proteins 0.000 description 9
- 102100020677 Krueppel-like factor 4 Human genes 0.000 description 9
- 229930182816 L-glutamine Natural products 0.000 description 9
- 102100038895 Myc proto-oncogene protein Human genes 0.000 description 9
- 101710163270 Nuclease Proteins 0.000 description 9
- 230000001594 aberrant effect Effects 0.000 description 9
- 210000003719 b-lymphocyte Anatomy 0.000 description 9
- 230000008859 change Effects 0.000 description 9
- 239000003797 essential amino acid Substances 0.000 description 9
- 235000020776 essential amino acid Nutrition 0.000 description 9
- 210000003494 hepatocyte Anatomy 0.000 description 9
- 102000018358 immunoglobulin Human genes 0.000 description 9
- 230000006698 induction Effects 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 239000013612 plasmid Substances 0.000 description 9
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 8
- 108010085895 Laminin Proteins 0.000 description 8
- 239000012980 RPMI-1640 medium Substances 0.000 description 8
- 230000003115 biocidal effect Effects 0.000 description 8
- 210000001671 embryonic stem cell Anatomy 0.000 description 8
- 238000003365 immunocytochemistry Methods 0.000 description 8
- 150000002500 ions Chemical class 0.000 description 8
- 239000003550 marker Substances 0.000 description 8
- 210000002569 neuron Anatomy 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 230000000717 retained effect Effects 0.000 description 8
- 241000894007 species Species 0.000 description 8
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 7
- 108090000978 Interleukin-4 Proteins 0.000 description 7
- 210000001744 T-lymphocyte Anatomy 0.000 description 7
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 7
- 230000027455 binding Effects 0.000 description 7
- 235000021186 dishes Nutrition 0.000 description 7
- 238000010362 genome editing Methods 0.000 description 7
- 210000000987 immune system Anatomy 0.000 description 7
- 230000005847 immunogenicity Effects 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- 239000003446 ligand Substances 0.000 description 7
- 108020004999 messenger RNA Proteins 0.000 description 7
- 230000002018 overexpression Effects 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 238000007480 sanger sequencing Methods 0.000 description 7
- 241000283690 Bos taurus Species 0.000 description 6
- 230000004568 DNA-binding Effects 0.000 description 6
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 6
- 108091092584 GDNA Proteins 0.000 description 6
- 101710135898 Myc proto-oncogene protein Proteins 0.000 description 6
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 108091023040 Transcription factor Proteins 0.000 description 6
- 102000040945 Transcription factor Human genes 0.000 description 6
- 101710150448 Transcriptional regulator Myc Proteins 0.000 description 6
- 238000011316 allogeneic transplantation Methods 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 239000013604 expression vector Substances 0.000 description 6
- 230000009368 gene silencing by RNA Effects 0.000 description 6
- 230000002068 genetic effect Effects 0.000 description 6
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 6
- 229910052737 gold Inorganic materials 0.000 description 6
- 239000010931 gold Substances 0.000 description 6
- 210000005260 human cell Anatomy 0.000 description 6
- 210000004153 islets of langerhan Anatomy 0.000 description 6
- 230000007774 longterm Effects 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 238000012216 screening Methods 0.000 description 6
- 210000001082 somatic cell Anatomy 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 210000000689 upper leg Anatomy 0.000 description 6
- 238000010354 CRISPR gene editing Methods 0.000 description 5
- 101001094700 Homo sapiens POU domain, class 5, transcription factor 1 Proteins 0.000 description 5
- 108700021430 Kruppel-Like Factor 4 Proteins 0.000 description 5
- 102000004058 Leukemia inhibitory factor Human genes 0.000 description 5
- 108090000581 Leukemia inhibitory factor Proteins 0.000 description 5
- 229930182555 Penicillin Natural products 0.000 description 5
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 5
- 102100024616 Platelet endothelial cell adhesion molecule Human genes 0.000 description 5
- 238000010240 RT-PCR analysis Methods 0.000 description 5
- 230000010632 Transcription Factor Activity Effects 0.000 description 5
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 5
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 5
- 239000012190 activator Substances 0.000 description 5
- 230000005875 antibody response Effects 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000002659 cell therapy Methods 0.000 description 5
- 230000002354 daily effect Effects 0.000 description 5
- 238000007405 data analysis Methods 0.000 description 5
- 238000012217 deletion Methods 0.000 description 5
- 230000037430 deletion Effects 0.000 description 5
- 238000012239 gene modification Methods 0.000 description 5
- 230000005017 genetic modification Effects 0.000 description 5
- 235000013617 genetically modified food Nutrition 0.000 description 5
- 210000001654 germ layer Anatomy 0.000 description 5
- 238000009396 hybridization Methods 0.000 description 5
- 238000002513 implantation Methods 0.000 description 5
- 230000015788 innate immune response Effects 0.000 description 5
- 238000002826 magnetic-activated cell sorting Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 210000002894 multi-fate stem cell Anatomy 0.000 description 5
- 230000035772 mutation Effects 0.000 description 5
- 230000036961 partial effect Effects 0.000 description 5
- 229940049954 penicillin Drugs 0.000 description 5
- 210000003583 retinal pigment epithelium Anatomy 0.000 description 5
- 239000012679 serum free medium Substances 0.000 description 5
- 238000010374 somatic cell nuclear transfer Methods 0.000 description 5
- 230000000638 stimulation Effects 0.000 description 5
- 229960005322 streptomycin Drugs 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 210000001685 thyroid gland Anatomy 0.000 description 5
- 210000002993 trophoblast Anatomy 0.000 description 5
- 230000003612 virological effect Effects 0.000 description 5
- 238000001262 western blot Methods 0.000 description 5
- 206010002091 Anaesthesia Diseases 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 238000011725 BALB/c mouse Methods 0.000 description 4
- 238000011728 BALB/c nude (JAX™ mouse strain) Methods 0.000 description 4
- 108020005004 Guide RNA Proteins 0.000 description 4
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 4
- 108060001084 Luciferase Proteins 0.000 description 4
- 239000005089 Luciferase Substances 0.000 description 4
- 229930040373 Paraformaldehyde Natural products 0.000 description 4
- 101150086694 SLC22A3 gene Proteins 0.000 description 4
- 241000282887 Suidae Species 0.000 description 4
- 238000010459 TALEN Methods 0.000 description 4
- 108010043645 Transcription Activator-Like Effector Nucleases Proteins 0.000 description 4
- 108090000631 Trypsin Proteins 0.000 description 4
- 102000004142 Trypsin Human genes 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- 108010023082 activin A Proteins 0.000 description 4
- 230000037005 anaesthesia Effects 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 238000012790 confirmation Methods 0.000 description 4
- 230000002950 deficient Effects 0.000 description 4
- 238000009795 derivation Methods 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000004520 electroporation Methods 0.000 description 4
- 210000002242 embryoid body Anatomy 0.000 description 4
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 210000003754 fetus Anatomy 0.000 description 4
- 230000006801 homologous recombination Effects 0.000 description 4
- 238000002744 homologous recombination Methods 0.000 description 4
- 238000003125 immunofluorescent labeling Methods 0.000 description 4
- 230000001506 immunosuppresive effect Effects 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 229960002725 isoflurane Drugs 0.000 description 4
- 229940021686 isothesia Drugs 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 210000003716 mesoderm Anatomy 0.000 description 4
- 210000003205 muscle Anatomy 0.000 description 4
- 229910052754 neon Inorganic materials 0.000 description 4
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 description 4
- 238000010899 nucleation Methods 0.000 description 4
- 229920002866 paraformaldehyde Polymers 0.000 description 4
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 description 4
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 230000014621 translational initiation Effects 0.000 description 4
- 239000012588 trypsin Substances 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 3
- 102000010825 Actinin Human genes 0.000 description 3
- 108010063503 Actinin Proteins 0.000 description 3
- 102000007469 Actins Human genes 0.000 description 3
- 108010085238 Actins Proteins 0.000 description 3
- 239000012103 Alexa Fluor 488 Substances 0.000 description 3
- AQGNHMOJWBZFQQ-UHFFFAOYSA-N CT 99021 Chemical compound CC1=CNC(C=2C(=NC(NCCNC=3N=CC(=CC=3)C#N)=NC=2)C=2C(=CC(Cl)=CC=2)Cl)=N1 AQGNHMOJWBZFQQ-UHFFFAOYSA-N 0.000 description 3
- 101100342337 Caenorhabditis elegans klf-1 gene Proteins 0.000 description 3
- 101100257372 Caenorhabditis elegans sox-3 gene Proteins 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- 241000699800 Cricetinae Species 0.000 description 3
- 102100031780 Endonuclease Human genes 0.000 description 3
- 241000282326 Felis catus Species 0.000 description 3
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 description 3
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 description 3
- 101000984042 Homo sapiens Protein lin-28 homolog A Proteins 0.000 description 3
- 206010062016 Immunosuppression Diseases 0.000 description 3
- 108010002616 Interleukin-5 Proteins 0.000 description 3
- 108020005196 Mitochondrial DNA Proteins 0.000 description 3
- 241001529936 Murinae Species 0.000 description 3
- 101100310657 Mus musculus Sox1 gene Proteins 0.000 description 3
- 101100310650 Mus musculus Sox18 gene Proteins 0.000 description 3
- 101100257376 Mus musculus Sox3 gene Proteins 0.000 description 3
- 241000209094 Oryza Species 0.000 description 3
- 235000007164 Oryza sativa Nutrition 0.000 description 3
- 102100025460 Protein lin-28 homolog A Human genes 0.000 description 3
- 238000011529 RT qPCR Methods 0.000 description 3
- 108020004459 Small interfering RNA Proteins 0.000 description 3
- 101150001847 Sox15 gene Proteins 0.000 description 3
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 3
- 108010017070 Zinc Finger Nucleases Proteins 0.000 description 3
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 238000010009 beating Methods 0.000 description 3
- 210000000988 bone and bone Anatomy 0.000 description 3
- 210000001185 bone marrow Anatomy 0.000 description 3
- 230000000747 cardiac effect Effects 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 210000000349 chromosome Anatomy 0.000 description 3
- 238000004140 cleaning Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 230000005782 double-strand break Effects 0.000 description 3
- 210000003981 ectoderm Anatomy 0.000 description 3
- 239000003623 enhancer Substances 0.000 description 3
- 210000004700 fetal blood Anatomy 0.000 description 3
- 230000001605 fetal effect Effects 0.000 description 3
- 231100000221 frame shift mutation induction Toxicity 0.000 description 3
- 230000037433 frameshift Effects 0.000 description 3
- 108020001507 fusion proteins Proteins 0.000 description 3
- 102000037865 fusion proteins Human genes 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 102000047279 human B2M Human genes 0.000 description 3
- 230000000415 inactivating effect Effects 0.000 description 3
- 210000005007 innate immune system Anatomy 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 210000000265 leukocyte Anatomy 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 210000004962 mammalian cell Anatomy 0.000 description 3
- AEMBWNDIEFEPTH-UHFFFAOYSA-N n-tert-butyl-n-ethylnitrous amide Chemical compound CCN(N=O)C(C)(C)C AEMBWNDIEFEPTH-UHFFFAOYSA-N 0.000 description 3
- 239000013642 negative control Substances 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 125000003729 nucleotide group Chemical group 0.000 description 3
- 210000002220 organoid Anatomy 0.000 description 3
- 239000012188 paraffin wax Substances 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 3
- 108091008146 restriction endonucleases Proteins 0.000 description 3
- 235000009566 rice Nutrition 0.000 description 3
- 238000012163 sequencing technique Methods 0.000 description 3
- 239000002356 single layer Substances 0.000 description 3
- 230000004936 stimulating effect Effects 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 238000010361 transduction Methods 0.000 description 3
- 230000026683 transduction Effects 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- 210000005166 vasculature Anatomy 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- LAQPKDLYOBZWBT-NYLDSJSYSA-N (2s,4s,5r,6r)-5-acetamido-2-{[(2s,3r,4s,5s,6r)-2-{[(2r,3r,4r,5r)-5-acetamido-1,2-dihydroxy-6-oxo-4-{[(2s,3s,4r,5s,6s)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxy}hexan-3-yl]oxy}-3,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy}-4-hydroxy-6-[(1r,2r)-1,2,3-trihydrox Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@H]([C@@H](NC(C)=O)C=O)[C@@H]([C@H](O)CO)O[C@H]1[C@H](O)[C@@H](O[C@]2(O[C@H]([C@H](NC(C)=O)[C@@H](O)C2)[C@H](O)[C@H](O)CO)C(O)=O)[C@@H](O)[C@@H](CO)O1 LAQPKDLYOBZWBT-NYLDSJSYSA-N 0.000 description 2
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 2
- VOUAQYXWVJDEQY-QENPJCQMSA-N 33017-11-7 Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)NCC(=O)NCC(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)CCC1 VOUAQYXWVJDEQY-QENPJCQMSA-N 0.000 description 2
- 239000012114 Alexa Fluor 647 Substances 0.000 description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 2
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 108010075254 C-Peptide Proteins 0.000 description 2
- 102000000905 Cadherin Human genes 0.000 description 2
- 108050007957 Cadherin Proteins 0.000 description 2
- 241000700198 Cavia Species 0.000 description 2
- 102000012422 Collagen Type I Human genes 0.000 description 2
- 108010022452 Collagen Type I Proteins 0.000 description 2
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 2
- 108010036949 Cyclosporine Proteins 0.000 description 2
- 241000701022 Cytomegalovirus Species 0.000 description 2
- 108010008532 Deoxyribonuclease I Proteins 0.000 description 2
- 102000007260 Deoxyribonuclease I Human genes 0.000 description 2
- 102100021238 Dynamin-2 Human genes 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 241000283086 Equidae Species 0.000 description 2
- 101150099612 Esrrb gene Proteins 0.000 description 2
- 108700039887 Essential Genes Proteins 0.000 description 2
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 2
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 2
- 102000008949 Histocompatibility Antigens Class I Human genes 0.000 description 2
- 108010088652 Histocompatibility Antigens Class I Proteins 0.000 description 2
- 102000018713 Histocompatibility Antigens Class II Human genes 0.000 description 2
- 108010027412 Histocompatibility Antigens Class II Proteins 0.000 description 2
- 101000817607 Homo sapiens Dynamin-2 Proteins 0.000 description 2
- 101001023379 Homo sapiens Lysosome-associated membrane glycoprotein 1 Proteins 0.000 description 2
- 101001109501 Homo sapiens NKG2-D type II integral membrane protein Proteins 0.000 description 2
- 241000701024 Human betaherpesvirus 5 Species 0.000 description 2
- 101150106931 IFNG gene Proteins 0.000 description 2
- 101150072501 Klf2 gene Proteins 0.000 description 2
- 101710098610 Leukocyte surface antigen CD47 Proteins 0.000 description 2
- 102100035133 Lysosome-associated membrane glycoprotein 1 Human genes 0.000 description 2
- 102000043129 MHC class I family Human genes 0.000 description 2
- 108091054437 MHC class I family Proteins 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 229930192392 Mitomycin Natural products 0.000 description 2
- 241000711408 Murine respirovirus Species 0.000 description 2
- 101100437231 Mus musculus B2m gene Proteins 0.000 description 2
- 101000937526 Mus musculus Beta-2-microglobulin Proteins 0.000 description 2
- 101001052030 Mus musculus Fibroblast growth factor 2 Proteins 0.000 description 2
- 101001021501 Mus musculus Hedgehog-interacting protein Proteins 0.000 description 2
- 101100508420 Mus musculus Ifng gene Proteins 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- 102100022680 NKG2-D type II integral membrane protein Human genes 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 102000008730 Nestin Human genes 0.000 description 2
- 108010088225 Nestin Proteins 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 102100035593 POU domain, class 2, transcription factor 1 Human genes 0.000 description 2
- 101710084414 POU domain, class 2, transcription factor 1 Proteins 0.000 description 2
- 102100035591 POU domain, class 2, transcription factor 2 Human genes 0.000 description 2
- 101710084411 POU domain, class 2, transcription factor 2 Proteins 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- 239000013614 RNA sample Substances 0.000 description 2
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 2
- 241000714474 Rous sarcoma virus Species 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 102000018679 Tacrolimus Binding Proteins Human genes 0.000 description 2
- 108010027179 Tacrolimus Binding Proteins Proteins 0.000 description 2
- 101150111019 Tbx3 gene Proteins 0.000 description 2
- 102000006601 Thymidine Kinase Human genes 0.000 description 2
- 102000013394 Troponin I Human genes 0.000 description 2
- 108010065729 Troponin I Proteins 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- 102000008790 VE-cadherin Human genes 0.000 description 2
- MIFGOLAMNLSLGH-QOKNQOGYSA-N Z-Val-Ala-Asp(OMe)-CH2F Chemical compound COC(=O)C[C@@H](C(=O)CF)NC(=O)[C@H](C)NC(=O)[C@H](C(C)C)NC(=O)OCC1=CC=CC=C1 MIFGOLAMNLSLGH-QOKNQOGYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000011543 agarose gel Substances 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 102000055104 bcl-X Human genes 0.000 description 2
- 108700000711 bcl-X Proteins 0.000 description 2
- 230000029918 bioluminescence Effects 0.000 description 2
- 238000005415 bioluminescence Methods 0.000 description 2
- 108010018828 cadherin 5 Proteins 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 239000013592 cell lysate Substances 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 230000001461 cytolytic effect Effects 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 210000001840 diploid cell Anatomy 0.000 description 2
- 230000003511 endothelial effect Effects 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 229940126864 fibroblast growth factor Drugs 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 230000004077 genetic alteration Effects 0.000 description 2
- 231100000118 genetic alteration Toxicity 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 238000010842 high-capacity cDNA reverse transcription kit Methods 0.000 description 2
- 230000005745 host immune response Effects 0.000 description 2
- 102000044459 human CD47 Human genes 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 238000011532 immunohistochemical staining Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 230000002452 interceptive effect Effects 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000008774 maternal effect Effects 0.000 description 2
- 229960004857 mitomycin Drugs 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 210000004165 myocardium Anatomy 0.000 description 2
- 210000005055 nestin Anatomy 0.000 description 2
- 230000006780 non-homologous end joining Effects 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 210000000287 oocyte Anatomy 0.000 description 2
- 210000004303 peritoneum Anatomy 0.000 description 2
- 230000008823 permeabilization Effects 0.000 description 2
- 125000005642 phosphothioate group Chemical group 0.000 description 2
- 230000035935 pregnancy Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 150000003212 purines Chemical class 0.000 description 2
- 229950010131 puromycin Drugs 0.000 description 2
- 150000003230 pyrimidines Chemical class 0.000 description 2
- 238000003762 quantitative reverse transcription PCR Methods 0.000 description 2
- 238000011536 re-plating Methods 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 238000009877 rendering Methods 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 230000001177 retroviral effect Effects 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 229940126586 small molecule drug Drugs 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 230000010474 transient expression Effects 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- 230000001960 triggered effect Effects 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 238000011179 visual inspection Methods 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- IVVNZDGDKPTYHK-JTQLQIEISA-N 1-cyano-2-[(2s)-3,3-dimethylbutan-2-yl]-3-pyridin-4-ylguanidine Chemical compound CC(C)(C)[C@H](C)N=C(NC#N)NC1=CC=NC=C1 IVVNZDGDKPTYHK-JTQLQIEISA-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
- HJCMDXDYPOUFDY-WHFBIAKZSA-N Ala-Gln Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O HJCMDXDYPOUFDY-WHFBIAKZSA-N 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 239000012099 Alexa Fluor family Substances 0.000 description 1
- 102100023635 Alpha-fetoprotein Human genes 0.000 description 1
- 239000004382 Amylase Substances 0.000 description 1
- 102000013142 Amylases Human genes 0.000 description 1
- 108010065511 Amylases Proteins 0.000 description 1
- 241000972773 Aulopiformes Species 0.000 description 1
- 241000701822 Bovine papillomavirus Species 0.000 description 1
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 1
- 210000001239 CD8-positive, alpha-beta cytotoxic T lymphocyte Anatomy 0.000 description 1
- 101100510263 Caenorhabditis elegans klf-3 gene Proteins 0.000 description 1
- 101100257359 Caenorhabditis elegans sox-2 gene Proteins 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 206010010144 Completed suicide Diseases 0.000 description 1
- 241000766026 Coregonus nasus Species 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 102000000311 Cytosine Deaminase Human genes 0.000 description 1
- 230000033616 DNA repair Effects 0.000 description 1
- 102100037126 Developmental pluripotency-associated protein 4 Human genes 0.000 description 1
- 241000255581 Drosophila <fruit fly, genus> Species 0.000 description 1
- 101100118093 Drosophila melanogaster eEF1alpha2 gene Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 108010042407 Endonucleases Proteins 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 241000700662 Fowlpox virus Species 0.000 description 1
- 101150112014 Gapdh gene Proteins 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
- 102400000321 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102100028970 HLA class I histocompatibility antigen, alpha chain E Human genes 0.000 description 1
- 102100028967 HLA class I histocompatibility antigen, alpha chain G Human genes 0.000 description 1
- 102100031546 HLA class II histocompatibility antigen, DO beta chain Human genes 0.000 description 1
- 108010024164 HLA-G Antigens Proteins 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 101710164669 Hedgehog-interacting protein Proteins 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 229920000209 Hexadimethrine bromide Polymers 0.000 description 1
- 241001272567 Hominoidea Species 0.000 description 1
- 101100437218 Homo sapiens B2M gene Proteins 0.000 description 1
- 101000983523 Homo sapiens Caspase-9 Proteins 0.000 description 1
- 101001033280 Homo sapiens Cytokine receptor common subunit beta Proteins 0.000 description 1
- 101000881868 Homo sapiens Developmental pluripotency-associated protein 4 Proteins 0.000 description 1
- 101000864646 Homo sapiens Dickkopf-related protein 1 Proteins 0.000 description 1
- 101000917237 Homo sapiens Fibroblast growth factor 10 Proteins 0.000 description 1
- 101001052035 Homo sapiens Fibroblast growth factor 2 Proteins 0.000 description 1
- 101000986085 Homo sapiens HLA class I histocompatibility antigen, alpha chain E Proteins 0.000 description 1
- 101000866281 Homo sapiens HLA class II histocompatibility antigen, DO beta chain Proteins 0.000 description 1
- 101000685824 Homo sapiens Probable RNA polymerase II nuclear localization protein SLC7A6OS Proteins 0.000 description 1
- 101000713275 Homo sapiens Solute carrier family 22 member 3 Proteins 0.000 description 1
- 101000851696 Homo sapiens Steroid hormone receptor ERR2 Proteins 0.000 description 1
- 101000666775 Homo sapiens T-box transcription factor TBX3 Proteins 0.000 description 1
- 101000837401 Homo sapiens T-cell leukemia/lymphoma protein 1A Proteins 0.000 description 1
- 101000825079 Homo sapiens Transcription factor SOX-13 Proteins 0.000 description 1
- 101000652736 Homo sapiens Transgelin Proteins 0.000 description 1
- 101000808011 Homo sapiens Vascular endothelial growth factor A Proteins 0.000 description 1
- 101000976622 Homo sapiens Zinc finger protein 42 homolog Proteins 0.000 description 1
- 101000857270 Homo sapiens Zinc finger protein GLIS1 Proteins 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 101710186643 Insulin-2 Proteins 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 1
- 241000581650 Ivesia Species 0.000 description 1
- 101150092727 KLF10 gene Proteins 0.000 description 1
- 101150023743 KLF9 gene Proteins 0.000 description 1
- 102100023972 Keratin, type II cytoskeletal 8 Human genes 0.000 description 1
- 108010070511 Keratin-8 Proteins 0.000 description 1
- 101150061181 Klf6 gene Proteins 0.000 description 1
- 108010017123 Kruppel-Like Transcription Factors Proteins 0.000 description 1
- 102000004434 Kruppel-Like Transcription Factors Human genes 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 108091054438 MHC class II family Proteins 0.000 description 1
- 102000043131 MHC class II family Human genes 0.000 description 1
- 241000282553 Macaca Species 0.000 description 1
- 241000829100 Macaca mulatta polyomavirus 1 Species 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 108700011259 MicroRNAs Proteins 0.000 description 1
- 241000713869 Moloney murine leukemia virus Species 0.000 description 1
- 241000713333 Mouse mammary tumor virus Species 0.000 description 1
- 101000981253 Mus musculus GPI-linked NAD(P)(+)-arginine ADP-ribosyltransferase 1 Proteins 0.000 description 1
- 101100510267 Mus musculus Klf4 gene Proteins 0.000 description 1
- 101000969137 Mus musculus Metallothionein-1 Proteins 0.000 description 1
- 101100137157 Mus musculus Pou5f1 gene Proteins 0.000 description 1
- 101100366231 Mus musculus Sox12 gene Proteins 0.000 description 1
- 101100310648 Mus musculus Sox17 gene Proteins 0.000 description 1
- 101100257363 Mus musculus Sox2 gene Proteins 0.000 description 1
- 101100043050 Mus musculus Sox4 gene Proteins 0.000 description 1
- 101100043062 Mus musculus Sox7 gene Proteins 0.000 description 1
- 101100043067 Mus musculus Sox8 gene Proteins 0.000 description 1
- 101100046526 Mus musculus Tnf gene Proteins 0.000 description 1
- 241000699667 Mus spretus Species 0.000 description 1
- 108091057508 Myc family Proteins 0.000 description 1
- 206010028470 Mycoplasma infections Diseases 0.000 description 1
- 108700026495 N-Myc Proto-Oncogene Proteins 0.000 description 1
- 102100030124 N-myc proto-oncogene protein Human genes 0.000 description 1
- 230000006051 NK cell activation Effects 0.000 description 1
- 238000002944 PCR assay Methods 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102100026466 POU domain, class 2, transcription factor 3 Human genes 0.000 description 1
- 101710084413 POU domain, class 2, transcription factor 3 Proteins 0.000 description 1
- 102100026459 POU domain, class 3, transcription factor 2 Human genes 0.000 description 1
- 101710133394 POU domain, class 3, transcription factor 2 Proteins 0.000 description 1
- 102100026456 POU domain, class 3, transcription factor 3 Human genes 0.000 description 1
- 101710133393 POU domain, class 3, transcription factor 3 Proteins 0.000 description 1
- 102100026450 POU domain, class 3, transcription factor 4 Human genes 0.000 description 1
- 101710133389 POU domain, class 3, transcription factor 4 Proteins 0.000 description 1
- 101150054854 POU1F1 gene Proteins 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 208000005764 Peripheral Arterial Disease Diseases 0.000 description 1
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 1
- 241001505332 Polyomavirus sp. Species 0.000 description 1
- 102100023136 Probable RNA polymerase II nuclear localization protein SLC7A6OS Human genes 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 101710150336 Protein Rex Proteins 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- 238000012193 PureLink RNA Mini Kit Methods 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108700005075 Regulator Genes Proteins 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 101150020367 SOX11 gene Proteins 0.000 description 1
- 101150073471 SOX14 gene Proteins 0.000 description 1
- 101150106167 SOX9 gene Proteins 0.000 description 1
- 101000849522 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 40S ribosomal protein S13 Proteins 0.000 description 1
- 108091081021 Sense strand Proteins 0.000 description 1
- 102000005157 Somatostatin Human genes 0.000 description 1
- 108010056088 Somatostatin Proteins 0.000 description 1
- 101150117830 Sox5 gene Proteins 0.000 description 1
- 102100036831 Steroid hormone receptor ERR2 Human genes 0.000 description 1
- 102100038409 T-box transcription factor TBX3 Human genes 0.000 description 1
- 102100028676 T-cell leukemia/lymphoma protein 1A Human genes 0.000 description 1
- 108700012920 TNF Proteins 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 108700009124 Transcription Initiation Site Proteins 0.000 description 1
- 102100022435 Transcription factor SOX-13 Human genes 0.000 description 1
- 102100031013 Transgelin Human genes 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- 102000044159 Ubiquitin Human genes 0.000 description 1
- 102100023550 Zinc finger protein 42 homolog Human genes 0.000 description 1
- 102100025883 Zinc finger protein GLIS1 Human genes 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 210000004504 adult stem cell Anatomy 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000000961 alloantigen Effects 0.000 description 1
- 108010026331 alpha-Fetoproteins Proteins 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 210000003663 amniotic stem cell Anatomy 0.000 description 1
- 235000019418 amylase Nutrition 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 208000005266 avian sarcoma Diseases 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 238000005422 blasting Methods 0.000 description 1
- 210000004703 blastocyst inner cell mass Anatomy 0.000 description 1
- 210000001109 blastomere Anatomy 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000011748 cell maturation Effects 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000003501 co-culture Methods 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 230000001332 colony forming effect Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 239000003398 denaturant Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229960000633 dextran sulfate Drugs 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 230000002222 downregulating effect Effects 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002900 effect on cell Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 210000004039 endoderm cell Anatomy 0.000 description 1
- 230000008753 endothelial function Effects 0.000 description 1
- 230000001973 epigenetic effect Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 210000000604 fetal stem cell Anatomy 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 230000003325 follicular Effects 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 101150003286 gata4 gene Proteins 0.000 description 1
- 238000001476 gene delivery Methods 0.000 description 1
- 238000003198 gene knock in Methods 0.000 description 1
- 238000003209 gene knockout Methods 0.000 description 1
- 230000030279 gene silencing Effects 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 210000005046 glial fibrillary acidic protein Anatomy 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000006481 glucose medium Substances 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 210000002443 helper t lymphocyte Anatomy 0.000 description 1
- 238000010562 histological examination Methods 0.000 description 1
- 238000001513 hot isostatic pressing Methods 0.000 description 1
- 102000055647 human CSF2RB Human genes 0.000 description 1
- 102000050762 human DKK1 Human genes 0.000 description 1
- 102000057243 human FGF10 Human genes 0.000 description 1
- 102000052983 human POU5F1 Human genes 0.000 description 1
- 102000058223 human VEGFA Human genes 0.000 description 1
- 210000004754 hybrid cell Anatomy 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000037451 immune surveillance Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000002650 immunosuppressive therapy Methods 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- ZGSXEXBYLJIOGF-BOPNQXPFSA-N iwr-1 Chemical compound C=1C=CC2=CC=CN=C2C=1NC(=O)C(C=C1)=CC=C1N1C(=O)[C@@H]2C(C=C3)CC3[C@@H]2C1=O ZGSXEXBYLJIOGF-BOPNQXPFSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000021633 leukocyte mediated immunity Effects 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 210000003738 lymphoid progenitor cell Anatomy 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 238000012083 mass cytometry Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 108091070501 miRNA Proteins 0.000 description 1
- 239000002679 microRNA Substances 0.000 description 1
- 239000011325 microbead Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 230000000869 mutational effect Effects 0.000 description 1
- 210000003643 myeloid progenitor cell Anatomy 0.000 description 1
- 210000003098 myoblast Anatomy 0.000 description 1
- 210000000944 nerve tissue Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 210000001020 neural plate Anatomy 0.000 description 1
- 210000001178 neural stem cell Anatomy 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 210000002747 omentum Anatomy 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 238000012247 phenotypical assay Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229960002310 pinacidil Drugs 0.000 description 1
- 230000003169 placental effect Effects 0.000 description 1
- 210000003240 portal vein Anatomy 0.000 description 1
- 238000010149 post-hoc-test Methods 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 238000002731 protein assay Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 102200015453 rs121912293 Human genes 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 230000003007 single stranded DNA break Effects 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- MFBOGIVSZKQAPD-UHFFFAOYSA-M sodium butyrate Chemical compound [Na+].CCCC([O-])=O MFBOGIVSZKQAPD-UHFFFAOYSA-M 0.000 description 1
- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229940048086 sodium pyrophosphate Drugs 0.000 description 1
- 210000001988 somatic stem cell Anatomy 0.000 description 1
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 1
- 229960000553 somatostatin Drugs 0.000 description 1
- 101150077014 sox10 gene Proteins 0.000 description 1
- 101150055666 sox6 gene Proteins 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000009168 stem cell therapy Methods 0.000 description 1
- 238000009580 stem-cell therapy Methods 0.000 description 1
- 125000002328 sterol group Chemical group 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000004114 suspension culture Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 235000019818 tetrasodium diphosphate Nutrition 0.000 description 1
- 239000001577 tetrasodium phosphonato phosphate Substances 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 239000005495 thyroid hormone Substances 0.000 description 1
- 229940036555 thyroid hormone Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 230000005030 transcription termination Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 238000012762 unpaired Student’s t-test Methods 0.000 description 1
- 230000002477 vacuolizing effect Effects 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
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0696—Artificially induced pluripotent stem cells, e.g. iPS
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/48—Reproductive organs
- A61K35/54—Ovaries; Ova; Ovules; Embryos; Foetal cells; Germ cells
- A61K35/545—Embryonic stem cells; Pluripotent stem cells; Induced pluripotent stem cells; Uncharacterised stem cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- C12N15/52—Genes encoding for enzymes or proenzymes
-
- 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
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
- C12N15/1138—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against receptors or cell surface proteins
-
- 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
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/50—Cell markers; Cell surface determinants
-
- 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
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/50—Cell markers; Cell surface determinants
- C12N2501/599—Cell markers; Cell surface determinants with CD designations not provided for elsewhere
-
- 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
- C12N2840/00—Vectors comprising a special translation-regulating system
- C12N2840/005—Vectors comprising a special translation-regulating system cell cycle specific
-
- 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
- C12N2840/00—Vectors comprising a special translation-regulating system
- C12N2840/007—Vectors comprising a special translation-regulating system cell or tissue specific
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y207/00—Transferases transferring phosphorus-containing groups (2.7)
- C12Y207/01—Phosphotransferases with an alcohol group as acceptor (2.7.1)
- C12Y207/01021—Thymidine kinase (2.7.1.21)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y305/00—Hydrolases acting on carbon-nitrogen bonds, other than peptide bonds (3.5)
- C12Y305/04—Hydrolases acting on carbon-nitrogen bonds, other than peptide bonds (3.5) in cyclic amidines (3.5.4)
- C12Y305/04001—Cytosine deaminase (3.5.4.1)
-
- 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)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Biomedical Technology (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Biotechnology (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- General Health & Medical Sciences (AREA)
- General Engineering & Computer Science (AREA)
- Developmental Biology & Embryology (AREA)
- Cell Biology (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Microbiology (AREA)
- Biochemistry (AREA)
- Transplantation (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Plant Pathology (AREA)
- Biophysics (AREA)
- Physics & Mathematics (AREA)
- Reproductive Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Virology (AREA)
- Epidemiology (AREA)
- Gynecology & Obstetrics (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
Description
ている。より好ましい実施形態では、前記β-2 ミクログロブリン・タンパク質が、配列番号1に対して少なくとも 90% の配列同一性を有する。より好ましい実施形態では、前記β-2 ミクログロブリン・タンパク質が、配列番号1の配列を有する。
タンパク質として知られている。)の発現も増加している。驚くべきことに、妊娠中の胎児の拒絶反応を防ぐのと同じトレランスが生じるメカニズムによって、本発明の HIP 細胞は拒絶反応を回避し、並びに、同種異系移植の後に、これらの細胞が長期生存し、及び生着することも可能になる。
C_000003.12:108043094-108094200 を有する。
ば、発現を阻害するか、又は標的分子若しくは標的タンパク質に結合する薬剤である。それらは部分的又は全体的に刺激を遮断するか、又はプロテアーゼ阻害剤活性を有することがある。それらは、記載の標的タンパク質の活性を、不活性化、脱感作、又はダウン・レギュレートすること等を含む、活性化を低下・減少(reduce)、減少(decrease)、阻害、又は遅延させることがある。調節剤は、標的分子又はタンパク質のアンタゴニストであることがある。
ィンガー・ヌクレアーゼは、ジンク・フィンガー DNA 結合ドメインを DNA 切断ドメインと融合することによって作製した人工的な制限酵素である。Zn フィンガー・ドメインを、特定の所望の DNA 配列を標的とするように、改変することができ、これによって、ジンク・フィンガー・ヌクレアーゼが複雑なゲノム内にただ一つだけある配列を標的とすること、が可能になる。内因性の DNA 修復機構を利用することにより、これらの試薬は、CRISPR や TALENs と同様に、高等生物のゲノムを正確に改変するために使用することができる。
は、MHC I 及び II(前記細胞がヒトの場合は HLA I 及び II)のタンパク質活性を減少させること又は無くすことを利用する。これは、それらの構成要素をコードする遺伝子を改変することによって行うことができる。ある実施形態では、前記遺伝子のコーディング領域又は調節配列を、CRISPR を用いて破壊する。別の実施形態では、干渉 RNA 技術を使用して遺伝子の翻訳を減少させる。第三の変化は、CD47 のようなマクロファージによる貪食作用に対する感受性を調節する遺伝子の変化であり、これは一般にウイルス技術を用いた遺伝子の「ノックイン」である。
する遺伝子と連結した、F36V 突然変異を有するヒト FK506 結合タンパク質(FKBP12)の配列を含む。FKBP12-F36V は、低分子二量体化剤である AP1903 に高い親和性で結合する。従って、本発明における iCasp9 の自殺機能は、二量体化の化学誘導剤(chemical inducer of dimerization(CID))を投与することによって引き起こされる。いくつかの実施形態では、前記 CID は低分子薬 AP1903 である。二量体化によって、アポトーシスが急速に誘導される(WO2011146862;Stasi et al, N. Engl. J. Med 365;18 (2011);Tey et al., Biol. Blood Marrow Transplant. 13:913-924 (2007) を参照のこと、それぞれは、その全体が参照により本明細書に取り込まれる)。
って、加湿インキュベーター中、37℃、20% O2、及び 5% CO2で維持した。ネオン・トランスフェクション・システム(Neon Transfection system)を用いて、4 種のリプログラミング因子 Oct4、KLF4、Sox2 及び c-Myc を発現するコドンを最適化した新規なミニ‐イントロン・プラスミド(co-MIP)(10-12 μmの DNA)を用いて、1×106個のマウス線維芽細胞をリプログラミングさせた。トランスフェクションをした後、線維芽細胞を MEF フィーダー層上に播種し、酪酸ナトリウム(0.2 mM)及び 50 μg/mL アスコルビン酸を添加した線維芽細胞培地中に置いた。ESC 様コロニーが出現したとき、培地を DMEM、20% FBS、L-グルタミン、非必須アミノ酸(NEAA)、β-メルカプトエタノール、及び 10 ng/mL 白血病抑制因子(LIF)を含むマウス iPSC 培地に変更した。2 代継代後、前記マウス iPSCs 細胞を 0.2% ゼラチン・コートしたプレートに移し、更に増殖させた。継代毎に、磁気活性化細胞選別(magnetic activated cell sorting(MACS))を使用して、前記 iPSCs をマウス多能性マーカー SSEA-1 に関して選別した。
ラチン(ミリポア)上で培養した。MycoAlert キット(ロンザ、ケルン、ドイツ)を用いて、細胞培養物をマイコプラズマ感染について定期的にスクリーニングした。
した組織培養プラスチック上に播種し、1 日おきに培地を交換した。4 日目の再播種に関して、細胞をバラバラに解離させ、5 ng/ml のマウス bFGF(ぺプロテック(Peprotech))を補充した RHB-A 培地中、ラミニン・コートした組織培養プラスチック上に、2×104細胞/cm2 で播種した。この時点から、細胞を 4 日毎に同じ条件で再播種し、培地を 2 日毎に交換し、全部で 20 日間培養した。各時点で分化しているニューロンの数を定量するために、24 ウェルの Nunc プレート中に置いたラミニン・コートしたガラス・カバーガラス上に、細胞を播種し、播種の2日後、培地を RHB-A :Neurobasal:B27 混合物(1:1:0.02)に変えて、分化したニューロンがより良く生き残るようにした。
た後、前記細胞を増殖させて、続けて多能性アッセイによる確認を行った。
Cs、及び miECs を確認した。
ARYLMGSMTPQAVLAFVALIPPTLPGTNIVLGALPEDRHIDRLAKRQRPGERLDLAMLAAIRRVYGLLANTVRYLQGGGSWWEDWGQLSGTAVPPQGAEPQSNAGPRPHIGDTLFTLFRAPELLAPNGDLYNVFAWALDVLAKRLRPMHVFILDYDQSPAGCRDALLQLTSGMVQTHVTTPGSIPTICDLARTFAREMGEAN
Claims (88)
- 以下を含む、低免疫原性多能性幹細胞を作製する方法: a.人工多能性幹細胞( iPSC )中にある B2M 遺伝子の両方の対立遺伝子の活性を無くすこと; b.前記 iPSC 中にある CIITA 遺伝子の両方の対立遺伝子の活性を無くすこと;及び c.前記 iPSC 中で CD47 の発現を増加させること。
- 前記 iPSC がヒトであり、前記 B2M 遺伝子がヒトであり、前記 CIITA 遺伝子がヒトであり、そして前記増加させた CD47 の発現が、プロモーターの制御下にあるヒト CD47 遺伝子の少なくとも 1 コピーを前記 iPSC 細胞に導入することから生じる、請求項1の方法。
- 前記 iPSC がマウスであり、前記 B2m 遺伝子がマウスであり、前記 Ciita 遺伝子がマウスであり、そして前記増加させた Cd47 の発現が、プロモーターの制御下にあるマウス Cd47 遺伝子の少なくとも 1 コピーを前記 iPSC 細胞に導入することから生じる、請求項1の方法。
- 前記プロモーターが構成的プロモーターである、請求項2又は3の何れか一項に記載の方法。
- 前記 B2M 遺伝子の両方の対立遺伝子における前記破壊が、前記 B2M 遺伝子の対立遺伝子の両方を破壊する、クラスターを形成し規則正しい間隔を持つ短いパリンドローム・リピート(Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 (CRISPR)反応で生じる、請求項1から3の何れか一項に記載の方法。
- 前記 CIITA 遺伝子の両方の対立遺伝子における前記破壊が、前記 CIITA 遺伝子の対立遺伝子の両方を破壊する CRISPR 反応で生じる、請求項1から3の何れか一項に記載の方法。
- 以下を含むヒト低免疫原性多能性(hHIP)幹細胞: a.内因性 B2M 遺伝子の両方の対立遺伝子を不活性化する 1 つ以上の改変; b.内因性 CIITA 遺伝子の両方の対立遺伝子を不活性化する 1 つ以上の改変;及び c.前記 hHIP 幹細胞中で CD47 遺伝子の発現を増加させる改変;ここで、前記 hHIP 幹細胞は、前記 B2M 及び CIITA の改変を含むが前記 CD47 遺伝子の発現の増加を含まない人工多能性幹細胞(iPSC)によって誘発される第 2 のナチュラル・キラー(NK)細胞応答よりも低い第 1 の NK 細胞応答を誘発し、並びに、ここで、前記第 1 及び第 2 の NK 細胞応答は、前記 hHIP 細胞又は前記 B2M 及び CIITA の改変のみを含む前記 iPSC 細胞の何れかと共に in vitro でインキュベートした NK 細胞からの IFN-γレベルを決定することによって測定される。
- 以下を含むヒト低免疫原性多能性(hHIP)幹細胞: a.内因性 B2M 遺伝子の両方の対立遺伝子を不活性化する 1 つ以上の改変; b.内因性 CIITA 遺伝子の両方の対立遺伝子を不活性化する 1 つ以上の改変;及び c.前記 hHIP 幹細胞中で CD47 遺伝子の発現を増加させる改変;ここで、前記 hHIP 幹細胞は、iPSC によって誘発される同種異系ヒト化マウス系統における第 2 の T 細胞応答よりも低い、前記ヒト化マウス系統における第 1 の T 細胞応答を誘発し、並びに、ここで、前記第 1 及び第 2 の T 細胞応答は、エリスポット・アッセイで、前記ヒト化マウスの脾細胞からの IFN-γレベルを決定することによって測定される。
- 請求項7又は8の何れか一項に記載の hHIP 幹細胞をヒト対象に移植することを含む方法。
- 以下を含む低免疫原性多能性細胞: a.親多能性細胞と比較した場合に、減少した内因性の主要組織適合抗原クラスI(HLA-I)機能; b.親多能性細胞と比較した場合に、減少した内因性の主要組織適合抗原クラスII(HLA-II)機能;及び c.NK 細胞による殺傷に対する感受性を減少させる CD47 機能の増大;ここで、前記低免疫原性多能性細胞は、前記 HLA-I 機能の減少、前記 HLA-II 機能の減少、及び NK 細胞による殺傷に対する感受性の減少の結果として、対象に移植されたときに拒絶反応を受けにくい。
- 前記 HLA-I 機能が、β-2 ミクログロブリン・タンパク質の発現を減少させることによって減少する、請求項10に記載の低免疫原性多能性細胞。
- 前記β-2 ミクログロブリン・タンパク質をコードする遺伝子がノックアウトされている、請求項11に記載の低免疫原性多能性細胞。
- 前記β-2 ミクログロブリン・タンパク質が、配列番号1に対して少なくとも 90% の配列同一性を有する、請求項12に記載の低免疫原性多能性細胞。
- 前記β-2 ミクログロブリン・タンパク質が、配列番号1の配列を有する、請求項13に記載の低免疫原性多能性細胞。
- 前記 HLA-I 機能が、HLA-A タンパク質の発現を減少させることによって減少する、請求項10に記載の低免疫原性多能性細胞。
- 前記 HLA-A タンパク質をコードする遺伝子がノックアウトされている、請求項15に記載の低免疫原性多能性細胞。
- 前記 HLA-I 機能が、HLA-B タンパク質の発現を減少させることによって減少する、請求項10に記載の低免疫原性多能性細胞。
- HLA-B タンパク質がノックアウトされている、請求項17に記載の低免疫原性多能性細胞。
- 前記 HLA-I 機能が、HLA-C タンパク質の発現を減少させることによって減少する、請求項10に記載の低免疫原性多能性細胞。
- 前記 HLA-C タンパク質をコードする遺伝子がノックアウトされている、請求項19に記載の低免疫原性多能性細胞。
- 前記低免疫原性多能性細胞が HLA-I 機能を含まない、請求項10から20の何れか一項に記載の低免疫原性多能性細胞。
- 前記 HLA-II 機能が、CIITA タンパク質の発現を減少させることによって減少する、請求項10から21の何れか一項に記載の低免疫原性多能性細胞。
- 前記 CIITA タンパク質をコードする遺伝子がノックアウトされている、請求項22に記載の低免疫原性多能性細胞。
- 前記 CIITA タンパク質が、配列番号2に対して少なくとも 90% の配列同一性を有する、請求項23に記載の低免疫原性多能性細胞。
- 前記 CIITA タンパク質が、配列番号2の配列を有する、請求項24に記載の低免疫原性多能性細胞。
- 前記 HLA-II 機能が、HLA-DP タンパク質の発現を減少させることによって減少する、請求項10から21の何れか一項に記載の低免疫原性多能性細胞。
- 前記 HLA-DP タンパク質をコードする遺伝子がノックアウトされている、請求項26に記載の低免疫原性多能性細胞。
- 前記 HLA-II 機能が、HLA-DR タンパク質の発現を減少させることによって減少する、請求項10から21の何れか一項に記載の低免疫原性多能性細胞。
- 前記 HLA-DR タンパク質をコードする遺伝子がノックアウトされている、請求項28に記載の低免疫原性多能性細胞。
- 前記 HLA-II 機能が、HLA-DQ タンパク質の発現を減少させることによって減少する、請求項10から21の何れか一項に記載の低免疫原性多能性細胞。
- 前記 HLA-DQ タンパク質をコードする遺伝子がノックアウトされている、請求項30に記載の低免疫原性多能性細胞。
- 前記低免疫原性多能性細胞が HLA-II 機能を含まない、請求項10から31の何れか一項に記載の低免疫原性多能性細胞。
- 前記 NK 細胞による殺傷に対する感受性の減少が、CD47 タンパク質の発現の増加によって引き起こされる、請求項10から32の何れか一項に記載の低免疫原性多能性細胞。
- 前記 CD47 タンパク質の発現の増加が、内因性 CD47 遺伝子座への改変から生じる、請求項33に記載の低免疫原性多能性細胞。
- 前記 CD47 タンパク質の発現の増加が、CD47 導入遺伝子から生じる、請求項33に記載の低免疫原性多能性細胞。
- 前記 CD47 タンパク質が、配列番号3に対して少なくとも 90% の配列同一性を有する、請求項33から35の何れか一項に記載の低免疫原性多能性細胞。
- 前記 CD47 タンパク質が、配列番号3の配列を有する、請求項27に記載の低免疫原性多能性細胞。
- 前記低免疫原性多能性細胞を死滅させる引き金によって活性化される自殺遺伝子を更に含む、請求項10から37の何れか一項に記載の低免疫原性多能性細胞。
- 前記自殺遺伝子が単純ヘルペス・ウイルス・チミジン・キナーゼ遺伝子(HSV-tk)であり、前記引き金がガンシクロビルである、請求項38に記載の低免疫原性多能性細胞。
- 前記 HSV-tk 遺伝子が、配列番号4に対して少なくとも 90% の配列同一性を含むタンパク質をコードする、請求項39に記載の低免疫原性多能性細胞。
- 前記 HSV-tk 遺伝子が、配列番号4の配列を含むタンパク質をコードする、請求項40に記載の低免疫原性多能性細胞。
- 前記自殺遺伝子が大腸菌シトシン・デアミナーゼ遺伝子(EC-CD)であり、前記引き金が 5-フルオロシトシン(5-FC)である、請求項38に記載の低免疫原性多能性細胞。
- 前記 EC-CD 遺伝子が、配列番号5に対して少なくとも 90% の配列同一性を含むタンパク質をコードする、請求項42に記載の低免疫原性多能性細胞。
- 前記 EC-CD 遺伝子が、配列番号5の配列を含むタンパク質をコードする、請求項43に記載の低免疫原性多能性細胞。
- 前記自殺遺伝子が誘導性カスパーゼ・タンパク質をコードし、前記引き金が二量体化への化学誘導剤(CID)である、請求項38に記載の低免疫原性多能性細胞。
- 前記遺伝子が、配列番号6に対して少なくとも 90% の配列同一性を含む誘導性カスパーゼ・タンパク質をコードする、請求項45に記載の低免疫原性多能性細胞。
- 前記遺伝子が、配列番号6の配列を含む誘導性カスパーゼ・タンパク質をコードする、請求項46に記載の低免疫原性多能性細胞。
- 前記 CID が AP1903 である、請求項45から47の何れか一項に記載の低免疫原性多能性細胞。
- 以下を含む低免疫原性多能性細胞の製造方法: a.多能性細胞中にある内因性の主要組織適合性抗原クラス I(HLA-I)機能を減少させる; b.多能性細胞中にある内因性の主要組織適合抗原クラ
ス II(HLA-II)機能を減少させる;及び c.NK 細胞による殺傷に対する前記多能性細胞の感受性を減少させるタンパク質の発現を増加させる。 - 前記 HLA-I 機能が、β-2 ミクログロブリン・タンパク質の発現を減少させることによって減少する、請求項49に記載の方法。
- 前記β-2 ミクログロブリン・タンパク質の発現が、前記β-2 ミクログロブリン・タンパク質をコードする遺伝子をノックアウトすることによって減少する、請求項50に記載の方法。
- 前記β-2 ミクログロブリン・タンパク質が、配列番号1と少なくとも 90% の配列同一性を有する、β-2 ミクログロブリン50。
- 前記β-2 ミクログロブリン・タンパク質が、配列番号1の配列を有する、β-2 ミクログロブリン51。
- 前記 HLA-I 機能が、HLA-A タンパク質発現の発現を減少させることによって減少する、請求項49に記載の方法。
- 前記 HLA-A タンパク質の発現が、前記 HLA-A タンパク質をコードする遺伝子をノックアウトすることによって減少する、請求項54に記載の方法。
- 前記 HLA-I 機能が、HLA-B タンパク質発現の発現を減少させることによって減少する、請求項49に記載の方法。
- 前記 HLA-B タンパク質発現が、前記 HLA-B タンパク質をコードする遺伝子をノックアウトすることにより減少する、請求項56に記載の方法。
- 前記 HLA-I 機能が、HLA-C タンパク質発現の発現を減少させることによって減少する、請求項49に記載の方法。
- 前記 HLA-C タンパク質発現が、前記 HLA-C タンパク質をコードする遺伝子をノックアウトすることにより減少する、請求項58に記載の方法。
- 前記低免疫原性多能性細胞が HLA-I 機能を含まない、請求項49から59の何れか一項に記載の方法。
- 前記 HLA-II 機能が、CIITA タンパク質の発現を減少させることによって減少する、請求項49から60の何れか一項に記載の方法。
- 前記 CIITA タンパク質の発現が、前記 CIITA タンパク質をコードする遺伝子をノックアウトすることによって減少する、請求項60に記載の方法。
- 前記 CIITA タンパク質が、配列番号2に対して少なくとも 90% の配列同一性を有する、請求項61に記載の方法。
- 前記 CIITA タンパク質が、配列番号2の配列を有する、請求項63に記載の方法。
- 前記 HLA-II 機能が、HLA-DP タンパク質の発現を減少させることによって減少する、請求項49から60の何れか一項に記載の方法。
- 前記 HLA-DP タンパク質の発現が、前記 HLA-DP タンパク質をコードする遺伝子をノックアウトすることにより減少する、請求項65に記載の方法。
- 前記 HLA-II 機能が、HLA-DR タンパク質の発現を減少させることによって減少する、請求項49から60の何れか一項に記載の方法。
- 前記 HLA-DR タンパク質の発現が、前記 HLA-DR タンパク質をコードする遺伝子をノックアウトすることにより減少する、請求項67に記載の方法。
- 前記 HLA-II 機能が、HLA-DQ タンパク質の発現を減少させることによって減少する、請求項49から60の何れか一項に記載の方法。
- 前記 HLA-DQ タンパク質の発現が、前記 HLA-DQ タンパク質をコードする遺伝子をノックアウトすることにより減少する、請求項69に記載の方法。
- 前記低免疫原性多能性細胞が HLA-II 機能を含まない、請求項49から70の何れか一項に記載の方法。
- 前記多能性細胞のマクロファージによる貪食作用に対する感受性を減少させるタンパク質の前記発現の増加が、内因性遺伝子座への改変により生じる、請求項49から71の何れか一項に記載の方法。
- 前記内因性遺伝子座が CD47 タンパク質をコードする、請求項72の方法。
- 前記タンパク質の発現の増加が導入遺伝子の発現により生じる、請求項49から71の何れか一項に記載の方法。
- 前記導入遺伝子が CD47 タンパク質をコードする、請求項74の方法。
- 前記 CD47 タンパク質が、配列番号3に対して少なくとも 90% の配列同一性を有する、請求項73又は74の何れか一項に記載の方法。
- 前記 CD47 タンパク質が、配列番号3の配列を有する、請求項76の方法。
- 前記低免疫原性多能性細胞を死滅させる引き金によって活性化される自殺遺伝子を発現させることを更に含む、請求項49から77の何れか一項に記載の方法。
- 前記自殺遺伝子が単純ヘルペス・ウイルス・チミジン・キナーゼ遺伝子(HSV-tk)であり、前記引き金がガンシクロビルである、請求項78の方法。
- 前記 HSV-tk 遺伝子が、配列番号4に対して少なくとも 90% の配列同一性を含むタンパク質をコードする、請求項79の方法。
- 前記 HSV-tk 遺伝子が、配列番号4の配列を含むタンパク質をコードする、請求項80の方法。
- 前記自殺遺伝子が大腸菌シトシン・デアミナーゼ遺伝子(EC-CD)であり、前記引き金が 5-フルオロシトシン(5-FC)である、請求項78に記載の方法。
- 前記 EC-CD 遺伝子が、配列番号5に対して少なくとも 90% の配列同一性を含むタンパク質をコードする、請求項82に記載の方法。
- 前記 EC-CD 遺伝子が、配列番号5の配列を含むタンパク質をコードする、請求項83に記載の方法。
- 前記自殺遺伝子が誘導性カスパーゼ・タンパク質をコードし、前記引き金が二量体化への特異的化学誘導剤(CID)である、請求項78に記載の方法。
- 前記遺伝子が、配列番号6に対して少なくとも 90% の配列同一性を含む誘導性カスパーゼ・タンパク質をコードする、請求項85に記載の方法。
- 前記遺伝子が、配列番号6の配列を含む誘導性カスパーゼ・タンパク質をコードする、請求項86に記載の方法。
- 前記 CID が AP1903 である、請求項85から87の何れか一項に記載の方法。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762445969P | 2017-01-13 | 2017-01-13 | |
US62/445,969 | 2017-01-13 | ||
PCT/US2018/013688 WO2018132783A1 (en) | 2017-01-13 | 2018-01-14 | Immunoengineered pluripotent cells |
JP2019538202A JP2020505025A (ja) | 2017-01-13 | 2018-01-14 | 免疫工学的な改変をした多能性細胞 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019538202A Division JP2020505025A (ja) | 2017-01-13 | 2018-01-14 | 免疫工学的な改変をした多能性細胞 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2023052079A true JP2023052079A (ja) | 2023-04-11 |
JP2023052079A5 JP2023052079A5 (ja) | 2023-06-19 |
Family
ID=61148505
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019538202A Pending JP2020505025A (ja) | 2017-01-13 | 2018-01-14 | 免疫工学的な改変をした多能性細胞 |
JP2022208126A Pending JP2023052079A (ja) | 2017-01-13 | 2022-12-26 | 免疫工学的な改変をした多能性細胞 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019538202A Pending JP2020505025A (ja) | 2017-01-13 | 2018-01-14 | 免疫工学的な改変をした多能性細胞 |
Country Status (12)
Country | Link |
---|---|
US (2) | US20190376045A1 (ja) |
EP (1) | EP3568464A1 (ja) |
JP (2) | JP2020505025A (ja) |
KR (1) | KR20190103373A (ja) |
CN (1) | CN110177869A (ja) |
AU (1) | AU2018207649A1 (ja) |
BR (1) | BR112019014257A2 (ja) |
CA (1) | CA3049766A1 (ja) |
EA (1) | EA201991692A1 (ja) |
IL (1) | IL267616A (ja) |
MX (1) | MX2019008413A (ja) |
WO (1) | WO2018132783A1 (ja) |
Families Citing this family (63)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2969847A1 (en) | 2014-12-10 | 2016-06-16 | Regents Of The University Of Minnesota | Genetically modified cells, tissues, and organs for treating disease |
EP3294342A4 (en) | 2015-05-08 | 2018-11-07 | President and Fellows of Harvard College | Universal donor stem cells and related methods |
AU2018237159A1 (en) | 2017-03-22 | 2019-09-05 | Intellia Therapeutics, Inc. | Compositions and methods for immunooncology |
EP3652312A1 (en) | 2017-07-14 | 2020-05-20 | Editas Medicine, Inc. | Systems and methods for targeted integration and genome editing and detection thereof using integrated priming sites |
US20210308183A1 (en) * | 2018-07-17 | 2021-10-07 | The Regents Of The University Of California | Chimeric antigen receptor t cells derived from immunoengineered pluripotent stem cells |
US10724052B2 (en) | 2018-09-07 | 2020-07-28 | Crispr Therapeutics Ag | Universal donor cells |
WO2020067993A1 (en) * | 2018-09-26 | 2020-04-02 | National University Of Singapore | Engineered human mesenchymal stromal cells with low immunogenicity, methods and kits of generating the same |
UY38427A (es) * | 2018-10-26 | 2020-05-29 | Novartis Ag | Métodos y composiciones para terapia con células oculares |
CN111424016A (zh) * | 2019-01-09 | 2020-07-17 | 复旦大学 | 降低细胞免疫原性的诱导型多能干细胞系及建立方法 |
AU2020223192A1 (en) * | 2019-02-15 | 2021-09-09 | President And Fellows Of Harvard College | Universal donor stem cells and related methods |
JP2022532174A (ja) * | 2019-05-10 | 2022-07-13 | 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 | 修飾多能性細胞 |
US11162079B2 (en) | 2019-05-10 | 2021-11-02 | The Regents Of The University Of California | Blood type O Rh-hypo-immunogenic pluripotent cells |
EP3990627A4 (en) | 2019-06-26 | 2023-07-19 | The Regents of The University of California | SIRP-ALPHA SILENCED NATURAL KILLER CELLS (NK) |
TW202115245A (zh) * | 2019-06-27 | 2021-04-16 | 丹麥商諾佛 儂迪克股份有限公司 | 安全免疫隱形細胞 |
WO2021004933A1 (en) | 2019-07-10 | 2021-01-14 | Kunz Helmuth Heinrich | Methods for deriving autologous and hypoimmunogenic hair follicle containing sheets in vitro |
EP4007596A1 (en) | 2019-08-01 | 2022-06-08 | Sana Biotechnology, Inc. | Dux4 expressing cells and uses thereof |
KR20220068222A (ko) | 2019-08-23 | 2022-05-25 | 사나 바이오테크놀로지, 인크. | Cd24 발현 세포 및 이의 용도 |
US11104918B2 (en) * | 2019-09-05 | 2021-08-31 | Crispr Therapeutics Ag | Universal donor cells |
US11116797B2 (en) | 2019-09-05 | 2021-09-14 | Crispr Therapeutics Ag | Universal donor cells |
JP2022547168A (ja) * | 2019-09-09 | 2022-11-10 | スクライブ・セラピューティクス・インコーポレイテッド | 免疫療法に使用するための組成物および方法 |
WO2021055985A1 (en) * | 2019-09-22 | 2021-03-25 | Cellerant Therapeutics, Inc. | Ipsc-derived, hypoimmunogenic, myeloid progenitor cells |
WO2021076427A1 (en) * | 2019-10-15 | 2021-04-22 | The Regents Of The University Of California | TRANSPLANTED CELL PROTECTION VIA Fc SEQUESTRATION |
CN116234906A (zh) | 2020-01-13 | 2023-06-06 | 萨那生物技术股份有限公司 | 血型抗原的修饰 |
JP2023510916A (ja) | 2020-01-17 | 2023-03-15 | サナ バイオテクノロジー,インコーポレイテッド | 遺伝子発現の制御のための安全スイッチ |
JP2023520997A (ja) | 2020-03-25 | 2023-05-23 | サナ バイオテクノロジー,インコーポレイテッド | 神経学的障害及び神経学的病態の処置のための低免疫原性神経細胞 |
AU2021259612A1 (en) * | 2020-04-21 | 2022-11-10 | Intima Bioscience, Inc. | Cellular vaccine platform and methods of use |
US20230338533A1 (en) * | 2020-05-15 | 2023-10-26 | Rxcell Inc. | Hypoimmunogenic Cells and Uses Thereof in Immune Responses |
KR20230074718A (ko) | 2020-08-13 | 2023-05-31 | 사나 바이오테크놀로지, 인크. | 저면역원성 세포로 감작된 환자를 치료하는 방법 및 관련 방법 및 조성물 |
CN112342196A (zh) * | 2020-08-18 | 2021-02-09 | 未来智人再生医学研究院(广州)有限公司 | 一种免疫兼容可逆的通用型多能干细胞及其应用 |
WO2022087019A1 (en) * | 2020-10-20 | 2022-04-28 | Replay Holdings, Llc | Methods and compositions for cellular therapy |
CN114457021A (zh) * | 2020-10-30 | 2022-05-10 | 未来智人再生医学研究院(广州)有限公司 | 一种表达cd47抗体的多能干细胞及其衍生物与应用 |
CN114525255A (zh) * | 2020-10-30 | 2022-05-24 | 未来智人再生医学研究院(广州)有限公司 | 一种表达il-11的多能干细胞衍生物及其应用 |
EP4251741A1 (en) | 2020-11-30 | 2023-10-04 | CRISPR Therapeutics AG | Gene-edited natural killer cells |
US11661459B2 (en) | 2020-12-03 | 2023-05-30 | Century Therapeutics, Inc. | Artificial cell death polypeptide for chimeric antigen receptor and uses thereof |
CN114107211A (zh) * | 2020-12-04 | 2022-03-01 | 未来智人再生医学研究院(广州)有限公司 | 一种多能干细胞及其衍生物 |
IL303473A (en) | 2020-12-31 | 2023-08-01 | Sana Biotechnology Inc | Methods and compositions for modulating CAR-T activity |
AU2021414617A1 (en) | 2020-12-31 | 2023-08-10 | Crispr Therapeutics Ag | Universal donor cells |
US20220296572A1 (en) | 2021-03-03 | 2022-09-22 | Sana Biotechnology, Inc. | Immunosuppressive therapies for use with cardiomyocyte cell therapies, and associated methods and compositions |
WO2022191216A1 (ja) * | 2021-03-09 | 2022-09-15 | 国立研究開発法人理化学研究所 | 低免疫原性網膜色素上皮細胞の製造方法 |
WO2022212393A1 (en) * | 2021-03-30 | 2022-10-06 | The Regents Of The University Of California | Transplanted cell protection via modified fc receptors |
KR20240011184A (ko) * | 2021-05-24 | 2024-01-25 | 상가모 테라퓨틱스, 인코포레이티드 | Ciita 표적화 아연 핑거 뉴클레아제 |
WO2022251367A1 (en) | 2021-05-27 | 2022-12-01 | Sana Biotechnology, Inc. | Hypoimmunogenic cells comprising engineered hla-e or hla-g |
WO2023287827A2 (en) | 2021-07-14 | 2023-01-19 | Sana Biotechnology, Inc. | Altered expression of y chromosome-linked antigens in hypoimmunogenic cells |
AU2022326565A1 (en) | 2021-08-11 | 2024-02-08 | Sana Biotechnology, Inc. | Genetically modified cells for allogeneic cell therapy |
KR20240053673A (ko) | 2021-08-11 | 2024-04-24 | 사나 바이오테크놀로지, 인크. | 저면역원성 세포 내 유전자 발현을 변경하기 위한 유도성 시스템 |
CA3227108A1 (en) | 2021-08-11 | 2023-02-16 | Xiaomeng HU | Genetically modified primary cells for allogeneic cell therapy |
WO2023019225A2 (en) | 2021-08-11 | 2023-02-16 | Sana Biotechnology, Inc. | Genetically modified cells for allogeneic cell therapy to reduce instant blood mediated inflammatory reactions |
AU2022325231A1 (en) | 2021-08-11 | 2024-02-08 | Sana Biotechnology, Inc. | Genetically modified cells for allogeneic cell therapy to reduce complement-mediated inflammatory reactions |
CN113801881B (zh) * | 2021-08-27 | 2024-02-20 | 浙江大学 | 超级增强子基因序列在促进人b2m基因表达中的用途 |
WO2023069790A1 (en) | 2021-10-22 | 2023-04-27 | Sana Biotechnology, Inc. | Methods of engineering allogeneic t cells with a transgene in a tcr locus and associated compositions and methods |
WO2023122337A1 (en) | 2021-12-23 | 2023-06-29 | Sana Biotechnology, Inc. | Chimeric antigen receptor (car) t cells for treating autoimmune disease and associated methods |
WO2023154578A1 (en) | 2022-02-14 | 2023-08-17 | Sana Biotechnology, Inc. | Methods of treating patients exhibiting a prior failed therapy with hypoimmunogenic cells |
WO2023158836A1 (en) | 2022-02-17 | 2023-08-24 | Sana Biotechnology, Inc. | Engineered cd47 proteins and uses thereof |
WO2023173123A1 (en) | 2022-03-11 | 2023-09-14 | Sana Biotechnology, Inc. | Genetically modified cells and compositions and uses thereof |
WO2023183313A1 (en) | 2022-03-22 | 2023-09-28 | Sana Biotechnology, Inc. | Engineering cells with a transgene in b2m or ciita locus and associated compositions and methods |
CN114958768B (zh) * | 2022-06-02 | 2023-03-24 | 健颐生物科技发展(山东)有限公司 | Fgf10旁分泌通用型人成纤维细胞制剂的制备方法 |
CN117343962A (zh) * | 2022-06-29 | 2024-01-05 | 中国科学院上海营养与健康研究所 | 免疫兼容型人多能干细胞、其制备方法及应用 |
WO2024003349A1 (en) | 2022-07-01 | 2024-01-04 | Novo Nordisk A/S | Enhancing neuronal differentiation of ventral midbrain neural progenitor cells |
CN117384851A (zh) * | 2022-07-11 | 2024-01-12 | 士泽生物医药(苏州)有限公司 | 一种表达faslg的通用型细胞及其制备方法 |
CN117431217A (zh) * | 2022-07-12 | 2024-01-23 | 上海驯鹿生物技术有限公司 | 表达靶向cd5的嵌合抗原受体(car)的细胞及其应用 |
GB202211117D0 (en) * | 2022-07-29 | 2022-09-14 | Replay Holdings Llc | Compositions and methods for non-immunogenecity |
GB202212144D0 (en) * | 2022-08-19 | 2022-10-05 | Resolution Therapeutics Ltd | Cells for therapy |
WO2024097315A2 (en) | 2022-11-02 | 2024-05-10 | Sana Biotechnology, Inc. | Cell therapy products and methods for producing same |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8724885D0 (en) | 1987-10-23 | 1987-11-25 | Binns M M | Fowlpox virus promotors |
DE19539493A1 (de) | 1995-10-24 | 1997-04-30 | Thomae Gmbh Dr K | Starker homologer Promotor aus Hamster |
EP3336188B1 (en) | 2008-09-22 | 2020-05-06 | Phio Pharmaceuticals Corp. | Reduced size self-delivering rnai compounds |
AU2010254811B2 (en) * | 2009-06-05 | 2015-02-19 | FUJIFILM Cellular Dynamics, Inc. | Reprogramming T cells and hematopoietic cells |
US9089520B2 (en) | 2010-05-21 | 2015-07-28 | Baylor College Of Medicine | Methods for inducing selective apoptosis |
US20150056225A1 (en) * | 2012-04-17 | 2015-02-26 | University Of Washington Through Its Center For Commercialization | HLA Class II Deficient Cells, HLA Class I Deficient Cells Capable of Expressing HLA Class II Proteins, and Uses Thereof |
US20170044500A1 (en) * | 2014-04-24 | 2017-02-16 | Board Of Regents, The University Of Texas System | Application of induced pluripotent stem cells to generate adoptive cell therapy products |
AU2016231061B2 (en) * | 2015-03-11 | 2020-11-26 | Cellectis | Methods for engineering allogeneic T cell to increase their persistence and/or engraftment into patients |
EP3294342A4 (en) * | 2015-05-08 | 2018-11-07 | President and Fellows of Harvard College | Universal donor stem cells and related methods |
WO2017079673A1 (en) * | 2015-11-04 | 2017-05-11 | Fate Therapeutics, Inc. | Genomic engineering of pluripotent cells |
-
2018
- 2018-01-14 US US16/476,794 patent/US20190376045A1/en active Pending
- 2018-01-14 JP JP2019538202A patent/JP2020505025A/ja active Pending
- 2018-01-14 BR BR112019014257A patent/BR112019014257A2/pt unknown
- 2018-01-14 KR KR1020197023696A patent/KR20190103373A/ko not_active IP Right Cessation
- 2018-01-14 MX MX2019008413A patent/MX2019008413A/es unknown
- 2018-01-14 EP EP18702859.2A patent/EP3568464A1/en active Pending
- 2018-01-14 EA EA201991692A patent/EA201991692A1/ru unknown
- 2018-01-14 CA CA3049766A patent/CA3049766A1/en active Pending
- 2018-01-14 WO PCT/US2018/013688 patent/WO2018132783A1/en unknown
- 2018-01-14 CN CN201880006714.XA patent/CN110177869A/zh active Pending
- 2018-01-14 AU AU2018207649A patent/AU2018207649A1/en active Pending
-
2019
- 2019-06-24 IL IL267616A patent/IL267616A/en unknown
-
2022
- 2022-12-26 JP JP2022208126A patent/JP2023052079A/ja active Pending
-
2023
- 2023-03-29 US US18/127,936 patent/US20230348862A1/en active Pending
Also Published As
Publication number | Publication date |
---|---|
US20190376045A1 (en) | 2019-12-12 |
IL267616A (en) | 2019-08-29 |
CA3049766A1 (en) | 2018-07-19 |
JP2020505025A (ja) | 2020-02-20 |
CN110177869A (zh) | 2019-08-27 |
BR112019014257A2 (pt) | 2020-04-28 |
EA201991692A1 (ru) | 2019-12-30 |
EP3568464A1 (en) | 2019-11-20 |
NZ754898A (en) | 2023-11-24 |
WO2018132783A1 (en) | 2018-07-19 |
US20230348862A1 (en) | 2023-11-02 |
AU2018207649A1 (en) | 2019-07-11 |
KR20190103373A (ko) | 2019-09-04 |
MX2019008413A (es) | 2019-09-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20230348862A1 (en) | Immunoengineered pluripotent cells | |
US20210308183A1 (en) | Chimeric antigen receptor t cells derived from immunoengineered pluripotent stem cells | |
Deuse et al. | Hypoimmunogenic derivatives of induced pluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients | |
US20200354673A1 (en) | Modified pluripotent cells | |
Telugu et al. | Porcine induced pluripotent stem cells analogous to naive and primed embryonic stem cells of the mouse | |
Huang et al. | A virus-free poly-promoter vector induces pluripotency in quiescent bovine cells under chemically defined conditions of dual kinase inhibition | |
US20240091274A1 (en) | TRANSPLANTED CELL PROTECTION VIA Fc SEQUESTRATION | |
JP2014520551A (ja) | 細胞のリプログラミング方法およびゲノムの改変方法 | |
Hansel et al. | The use of induced pluripotent stem cells for the study and treatment of liver diseases | |
US11162079B2 (en) | Blood type O Rh-hypo-immunogenic pluripotent cells | |
CN116234906A (zh) | 血型抗原的修饰 | |
JP2021509577A (ja) | Crispr活性化による人工多能性細胞の生成 | |
JP2024515037A (ja) | 改変Fc受容体による移植細胞保護 | |
Hu et al. | HYPOIMMUNOGENIC DERIVATIVES OF INDUCED PLURIPOTENT STEM CELLS EVADE | |
CN117279651A (zh) | 通过修饰的Fc受体的移植细胞保护 | |
AU2020307550A1 (en) | SIRPalpha-silenced natural killer (NK) cells |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230124 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20230124 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230609 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20231212 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20240311 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20240510 |