CN1333691A - 用于治疗影响神经干细胞或祖细胞的病症的药用产品及方法 - Google Patents
用于治疗影响神经干细胞或祖细胞的病症的药用产品及方法 Download PDFInfo
- Publication number
- CN1333691A CN1333691A CN99815708A CN99815708A CN1333691A CN 1333691 A CN1333691 A CN 1333691A CN 99815708 A CN99815708 A CN 99815708A CN 99815708 A CN99815708 A CN 99815708A CN 1333691 A CN1333691 A CN 1333691A
- Authority
- CN
- China
- Prior art keywords
- cell
- disease
- growth hormone
- patient
- purposes
- 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
- 238000000034 method Methods 0.000 title claims abstract description 38
- 238000011282 treatment Methods 0.000 title claims abstract description 25
- 229940126601 medicinal product Drugs 0.000 title claims abstract description 18
- 210000001178 neural stem cell Anatomy 0.000 title claims abstract description 8
- 210000005155 neural progenitor cell Anatomy 0.000 title claims abstract description 7
- 102000018997 Growth Hormone Human genes 0.000 claims abstract description 68
- 108010051696 Growth Hormone Proteins 0.000 claims abstract description 68
- 239000000122 growth hormone Substances 0.000 claims abstract description 68
- 210000004027 cell Anatomy 0.000 claims abstract description 57
- 210000000130 stem cell Anatomy 0.000 claims abstract description 40
- 210000002569 neuron Anatomy 0.000 claims abstract description 32
- 210000004248 oligodendroglia Anatomy 0.000 claims abstract description 26
- 230000001965 increasing effect Effects 0.000 claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 238000000338 in vitro Methods 0.000 claims abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 38
- 201000010099 disease Diseases 0.000 claims description 37
- 210000003169 central nervous system Anatomy 0.000 claims description 35
- 239000000463 material Substances 0.000 claims description 35
- 230000006378 damage Effects 0.000 claims description 26
- 230000006870 function Effects 0.000 claims description 22
- 210000004498 neuroglial cell Anatomy 0.000 claims description 18
- 210000004556 brain Anatomy 0.000 claims description 14
- 210000001428 peripheral nervous system Anatomy 0.000 claims description 12
- 210000003050 axon Anatomy 0.000 claims description 10
- 210000005036 nerve Anatomy 0.000 claims description 10
- 230000002950 deficient Effects 0.000 claims description 8
- 239000013543 active substance Substances 0.000 claims description 7
- 108090000623 proteins and genes Proteins 0.000 claims description 5
- 238000010254 subcutaneous injection Methods 0.000 claims description 5
- 239000007929 subcutaneous injection Substances 0.000 claims description 5
- 102100020948 Growth hormone receptor Human genes 0.000 claims description 4
- 206010021143 Hypoxia Diseases 0.000 claims description 4
- 208000027418 Wounds and injury Diseases 0.000 claims description 4
- 201000006417 multiple sclerosis Diseases 0.000 claims description 4
- 102000004169 proteins and genes Human genes 0.000 claims description 4
- 230000000472 traumatic effect Effects 0.000 claims description 4
- 208000000044 Amnesia Diseases 0.000 claims description 3
- 208000016192 Demyelinating disease Diseases 0.000 claims description 3
- 208000018737 Parkinson disease Diseases 0.000 claims description 3
- 208000015114 central nervous system disease Diseases 0.000 claims description 3
- 210000002932 cholinergic neuron Anatomy 0.000 claims description 3
- 230000003828 downregulation Effects 0.000 claims description 3
- 230000001146 hypoxic effect Effects 0.000 claims description 3
- 238000010255 intramuscular injection Methods 0.000 claims description 3
- 239000007927 intramuscular injection Substances 0.000 claims description 3
- 208000037906 ischaemic injury Diseases 0.000 claims description 3
- 231100000863 loss of memory Toxicity 0.000 claims description 3
- 230000001537 neural effect Effects 0.000 claims description 3
- 208000001738 Nervous System Trauma Diseases 0.000 claims description 2
- 230000000975 bioactive effect Effects 0.000 claims description 2
- 238000001802 infusion Methods 0.000 claims description 2
- 238000001990 intravenous administration Methods 0.000 claims description 2
- 208000028412 nervous system injury Diseases 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 238000002054 transplantation Methods 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims 4
- 210000004958 brain cell Anatomy 0.000 claims 3
- 206010019196 Head injury Diseases 0.000 claims 2
- 108010068542 Somatotropin Receptors Proteins 0.000 claims 2
- 230000002942 anti-growth Effects 0.000 claims 2
- 230000009514 concussion Effects 0.000 claims 2
- 230000002536 noncholinergic effect Effects 0.000 claims 2
- 210000000278 spinal cord Anatomy 0.000 claims 2
- 230000004071 biological effect Effects 0.000 claims 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 6
- 230000001939 inductive effect Effects 0.000 abstract description 5
- 230000002159 abnormal effect Effects 0.000 abstract 1
- 210000001130 astrocyte Anatomy 0.000 abstract 1
- 230000003247 decreasing effect Effects 0.000 abstract 1
- 238000001727 in vivo Methods 0.000 abstract 1
- 210000003061 neural cell Anatomy 0.000 abstract 1
- 230000001902 propagating effect Effects 0.000 abstract 1
- 241001465754 Metazoa Species 0.000 description 18
- 241000700159 Rattus Species 0.000 description 16
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 14
- XUIIKFGFIJCVMT-LBPRGKRZSA-N L-thyroxine Chemical compound IC1=CC(C[C@H]([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-LBPRGKRZSA-N 0.000 description 10
- 210000001947 dentate gyrus Anatomy 0.000 description 10
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 10
- 229950008325 levothyroxine Drugs 0.000 description 10
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 8
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 8
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 8
- 229960004544 cortisone Drugs 0.000 description 8
- 230000004069 differentiation Effects 0.000 description 7
- 238000011534 incubation Methods 0.000 description 7
- 230000001172 regenerating effect Effects 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 230000004663 cell proliferation Effects 0.000 description 5
- 229960000890 hydrocortisone Drugs 0.000 description 5
- 238000004900 laundering Methods 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 238000012545 processing Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- XUIIKFGFIJCVMT-GFCCVEGCSA-N D-thyroxine Chemical compound IC1=CC(C[C@@H](N)C(O)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-GFCCVEGCSA-N 0.000 description 4
- 230000002490 cerebral effect Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 210000001320 hippocampus Anatomy 0.000 description 4
- 229940034208 thyroxine Drugs 0.000 description 4
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 3
- 102000013275 Somatomedins Human genes 0.000 description 3
- 238000009395 breeding Methods 0.000 description 3
- 230000001488 breeding effect Effects 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- 210000003714 granulocyte Anatomy 0.000 description 3
- 230000000971 hippocampal effect Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 208000020431 spinal cord injury Diseases 0.000 description 3
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 3
- 102100033367 Appetite-regulating hormone Human genes 0.000 description 2
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 2
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 208000028389 Nerve injury Diseases 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical class O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 2
- 230000003412 degenerative effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000007667 floating Methods 0.000 description 2
- 108010077689 gamma-aminobutyryl-2-methyltryptophyl-2-methyltryptophyl-2-methyltryptophyl-lysinamide Proteins 0.000 description 2
- 238000010166 immunofluorescence Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 230000008764 nerve damage Effects 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 230000008447 perception Effects 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 230000008929 regeneration Effects 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010002660 Anoxia Diseases 0.000 description 1
- 241000976983 Anoxia Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 102000009024 Epidermal Growth Factor Human genes 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- 241000283074 Equus asinus Species 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- 101710099093 Growth hormone receptor Proteins 0.000 description 1
- BGSOJVFOEQLVMH-UHFFFAOYSA-N Hydrocortisone phosphate Natural products O=C1CCC2(C)C3C(O)CC(C)(C(CC4)(O)C(=O)COP(O)(O)=O)C4C3CCC2=C1 BGSOJVFOEQLVMH-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- SXEHKFHPFVVDIR-UHFFFAOYSA-N [4-(4-hydrazinylphenyl)phenyl]hydrazine Chemical compound C1=CC(NN)=CC=C1C1=CC=C(NN)C=C1 SXEHKFHPFVVDIR-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000007953 anoxia Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000003376 axonal effect Effects 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 210000002318 cardia Anatomy 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 210000003591 cerebellar nuclei Anatomy 0.000 description 1
- BGSOJVFOEQLVMH-VWUMJDOOSA-N cortisol phosphate Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)COP(O)(O)=O)[C@@H]4[C@@H]3CCC2=C1 BGSOJVFOEQLVMH-VWUMJDOOSA-N 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 210000005064 dopaminergic neuron Anatomy 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 108091005608 glycosylated proteins Proteins 0.000 description 1
- 102000035122 glycosylated proteins Human genes 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 229950000785 hydrocortisone phosphate Drugs 0.000 description 1
- VWQWXZAWFPZJDA-CGVGKPPMSA-N hydrocortisone succinate Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)COC(=O)CCC(O)=O)[C@@H]4[C@@H]3CCC2=C1 VWQWXZAWFPZJDA-CGVGKPPMSA-N 0.000 description 1
- 230000002055 immunohistochemical effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 210000005171 mammalian brain Anatomy 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000007971 neurological deficit Effects 0.000 description 1
- 230000006576 neuronal survival Effects 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 235000008476 powdered milk Nutrition 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000008521 reorganization Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 210000004116 schwann cell Anatomy 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 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 1
- 229940088542 solu-cortef Drugs 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 238000011476 stem cell transplantation Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000009182 swimming Effects 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000007492 two-way ANOVA Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 210000004885 white matter Anatomy 0.000 description 1
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
- C12N5/0618—Cells of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/27—Growth hormone [GH], i.e. somatotropin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
-
- 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
- C12N2501/30—Hormones
- C12N2501/305—Growth hormone [GH], aka. somatotropin
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Zoology (AREA)
- General Health & Medical Sciences (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Animal Behavior & Ethology (AREA)
- Endocrinology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Wood Science & Technology (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Cell Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- General Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
一种物质用于生产治疗影响神经干细胞、祖细胞和/或衍生自神经干细胞或祖细胞的细胞的病症、特别是影响少突神经胶质细胞、星形神经胶质细胞和/或神经元细胞的病症的药用产品的用途,其中所述物质给予时使诸如生长激素、其功能相当的类似物的生长激素浓度增加,或者所述物质使内源性生长激素释放增加。通过给予所述细胞一种增加生长激素浓度的物质,从而体外或体内诱导谱系定向、繁殖和/或诱导或保持由祖细胞、干细胞和/或衍生自祖细胞、干细胞的细胞产生神经元、少突神经胶质细胞、星形神经胶质细胞的方法。本发明还公开了减少由祖细胞或干细胞产生少突神经胶质细胞、神经元、星形神经胶质细胞的方法,其中给予所述患者药学有效量的使生长激素或其功能相当类似物浓度降低的物质。
Description
技术领域
本发明涉及用于生产药用产品的物质,所述物质给予患者时使生长激素浓度增加。
本发明还涉及治疗影响神经干细胞或祖细胞的病症的方法。
发明背景
人类中枢神经***(CNS)的创伤性、窒息性、缺氧性、局部缺血性、中毒性、感染性、退化性或代谢性损伤可引起几种不同细胞类型某种程度的损害。创伤、窒息、毒素、局部缺血或感染对大脑的损害常常引起神经病性缺陷和认知性缺陷。退化性疾病可引起特定细胞群的丧失。如帕金森氏病与黑质中的多巴胺能神经元的特异性丧失有关,同样,多发性硬化症与髓磷质和少突神经胶质细胞的丧失有关。特定类型神经元的选择性丧失引起的退化性病症的其它实例为与胆碱能神经元丧失有关的Alzheimer病。还有许多CNS损伤或疾病能引起少突神经胶质细胞、星形神经胶质细胞或神经元细胞损害的其它情况。
此外,已发现少突神经胶质细胞表达的表面分子抑制中枢神经***白质束中轴索损伤和脊髓损伤后轴索的再生和萌芽。
祖细胞随如表皮生长因子(EGF)的生长因子生长和繁殖,表皮生长因子属于不同于GH的一类物质。
总而言之,哺乳动物脑组织变性或损害后没有替换神经元的特性。因此认为神经元的丧失是永久性的。关于海马结构的粒细胞层描述了出生后神经发生延长(Altman,J.和Das,G.D.,J.Comp.Neurol.124:319-335(1965);Altman,J.和Das,G.D.,Nature 214:1098-1101(1967);Caviness,V.S.Jr.,J.Comp Neurol.151:113-120(1973);Gueneau,G.,Privat,A.,Drouet,J.和Court,L.,Dev.Neurosci.5,345-358(1982);Eckenhoff,M.F.和Rakic,P.,J.Neurosci.8:2729-2747(1988))。最近证实人类神经发生一直持续到成人期(Eriksson,P.S.,Perfilieva,E.,Rjrk-Eriksson,T.,Alborn,A.,Nordborg,C.,Peterson,D.A.,Gage,F.H.,Nature Med.出版中)。神经元祖细胞位于齿状回的分颗粒区(subgranularzone,SGZ),在此它们持续增殖、移行入粒细胞层中并分化成各种粒细胞(Kuhn,H.,Dickinson-Anson,H.和Gage,F.H.,J.Neurosci.16:2027-2033(1996);Cameron,H.A,Wooley,C.S.,McEwen,B.S.和Gould,E.,Neuroscience 56:337-344(1933);Seki,T.和Arai,Y.,J.Neurosci.13:2351-2358(1933))。所述粒细胞层中的这些新生神经元表达分化的神经元的标志物并具有相当于分化的各类粒细胞的形态特点(Kaplan,M.S.和Bell,D.H.,J.Neurosci.4:1429-1411(1984);Cameron,H.A.,Woolley,C.S.,McEwen,B.S.和Gould,E.Neuroscience 56:337-344(1993);Cameron,H.A.,Woolley,C.S.和Gould,E.,Brain Res.611:342-346(1993))。此外,它们将轴索过程转换成苔鲜纤维途径并与其海马CA3的靶组织形成突触连接(Seki,T.和Arai,Y.,J.Neurosci.13:2351-2358(1993);Stanfield,B.B.和Trice,J.E.Exp.Brain Res.72:399-406(1988)。海马与空间感知和记忆有关(McNamara,R.K.和Skelton,R.W.,Brain Res.Rev.18:33-49(1993))。给予n-甲基-d-天门冬氨酸(NMDA)受体拮抗剂或去除肾上腺可影响祖细胞的增殖(Cameron,H.A.和Gould,E.Neuroscience 61:203-209(1994);Cameron,H.A.,Tanapat,P.和Gould,E.,Neuroscience 82:349-354(1998))。随着年龄增长可塑性降低,并且最近的研究证实,随年龄增长祖细胞的增殖也减少但不是完全消除(Kuhn,H.,Dickinson-Anson,H.和Gage,F.H.,J.Neurosci.16:2027-2033(1996))。最近将从成年啮齿动物脑中分离的干细胞移植到成年动物的脑中,在成年动物脑中这些干细胞分化成具有神经元特点的细胞(Suhonen,J.O.,Peterson,D.A.,Ray,J.和Gage,F.H.,Nature 383:624-627(1996)。
此外,已表明丰富环境促进幼鼠齿状回的神经发生。表明处于丰富环境导致新形成的粒细胞神经元存活数量增加,以及齿状回神经元总数增加(Kempermann,G.,Kuhn,H.G.和Gage,F.H.,Nature 386:493-495(1997))。
发明概述
目前发现使用生长激素或其类似物或另一种导致生长激素或其类似物浓度增加的物质,调节来自成人CNS的神经干细胞和祖细胞的增殖和/或分化是可能的。因此本发明提供治疗主要影响少突神经胶质细胞、星形神经胶质细胞或神经元细胞的中枢神经***损伤或中枢神经***疾病的新的可能性,所述治疗调节中枢神经***中增殖细胞的发生和/或神经元干细胞或祖细胞的分化。
还发现控制干细胞、祖细胞和具有产生神经元、星形神经胶质细胞或少突神经胶质细胞潜力的其它细胞、特别是源自中枢神经***细胞的体外增殖是可能的。此类细胞可例如用于患者的治疗。
因此,本发明涉及使用一种物质的生产治疗影响神经干细胞和/或祖细胞的病症的药用产品,所述物质给予患者时将使生长激素或其功能相当的类似物浓度增加。
本发明还涉及治疗影响神经干细胞和/或祖细胞的病症的方法,此方法中,给予患者将使生长激素或其功能相当的类似物浓度增加的药学有效量的物质。
此外,本发明涉及一种诱导祖细胞、干细胞和/或衍生自祖细胞、干细胞的细胞谱系定向(lineage determination)、繁殖和/或诱导或保持产生神经元、少突神经胶质细胞、星形神经胶质细胞的方法,该方法在体外给予干细胞、祖细胞、神经元星形神经胶质细胞和/或少突神经胶质细胞有效量的生长激素或其功能相当的类似物。
本发明的另一方面涉及缘于CNS中生长激素浓度过高引起的CNS病症。
因此本发明还涉及使用一种物质生产治疗影响干细胞、祖细胞和/或衍生自干细胞或祖细胞的细胞的病症的药用产品的方法,所述物质给予患者时将使生长激素或其功能相当的类似物浓度下降,以及本发明涉及减少患者中枢或外周神经***中的或衍生自中枢或外周神经***的祖细胞或干细胞产生少突神经胶质细胞、神经元、星形神经胶质细胞的方法,其中给予所述患者药学有效量的使生长激素或其功能相当的类似物浓度降低的物质。
由以下描述和所附权利要求书可了解本发明的特征性特点。
本发明详述
包括人脑在内的哺乳动物的脑组织终生保持其在脑的某些区域产生神经元的能力。新的神经元和星形神经胶质细胞以及少突神经胶质细胞由干细胞或祖细胞通过细胞发生产生。在完成本发明的研究过程中发现生长激素(以下以GH表示)使成年脑中从祖细胞/干细胞的细胞发生增加。还发现海马新生细胞数量的增加与学习和记忆的改善有关。这些发现使得我们认识到:通过控制存在于所述细胞周围环境中的GH含量,控制患者神经病学缺陷如记忆和学习缺陷是可能的。
因此发现通过增加包括神经元、星形神经胶质细胞以及少突神经胶质细胞在内的干细胞或祖细胞衍生细胞数量治疗创伤后CNS损伤或缺陷是可能的。
还发现通过提高患者GH浓度以诱导干细胞增殖和/或分化,同时增加细胞发生,从而增加患者包括神经元、星形神经胶质细胞以及少突神经胶质细胞在内的干细胞或祖细胞衍生细胞的数量,治疗CNS损伤后所引起的神经损伤是可能的。
最后发现通过提高患者GH浓度以诱导干细胞增殖和/或分化,同时增加细胞产生,从而增加患者包括神经元、星形神经胶质细胞以及少突神经胶质细胞在内的干细胞或祖细胞衍生细胞的数量,以便有助于通过手术切除分离含所述细胞的脑组织小样本,以进一步在体外扩增,并再移植入所述患者体内,而治疗CNS损伤后所引起的神经损伤是可能的。
因此,本发明涉及使用一种物质生产治疗影响神经干细胞或祖细胞和/或衍生自神经干细胞或祖细胞的细胞的病症的药用产品,所述物质给予患者时将使生长激素或其类似物浓度增加,以及本发明涉及治疗影响神经干细胞、祖细胞和/或衍生自神经干细胞或祖细胞的细胞的病症的方法,其中给予患者使生长激素浓度增加的药学有效量的一种物质。
使生长激素浓度增加的物质或其类似物可以为例如生长激素本身或其功能相当的类似物。术语“其功能相当的类似物”涉及所有当给予患者时具有与GH基本相同的生物学和药理学作用的物质。这样的类似物可以是例如合成的GH模拟物。也可以使用一种化合物,所述化合物当给予患者时例如通过使内源性GH释放增加,从而使患者CNS的GH或天然GH类似物或其介质(mediator)的有效浓度增加。例如,可使用正向调节GH结合蛋白,如GH释放物质生长激素释放肽(GHRP)及其类似物。
按照本发明的药用产品最好是所述活性物质包含于诸如本领域已知的那些药学上可接受的载体或稀释剂中。
按照本发明使用的所述药用产品或物质优选通过静脉内外周输注或通过肌内或皮下注射给予患者。还可以通过手术***的分流管将所述药用产品或药用活性物质给予到患者脑室。
优选皮下给予的所述药学活性物质剂量为每周约0.01-1IE/kg患者体重。
本文所用术语“患者”是指需要按照本发明的治疗的任何人或非人类哺乳动物。
本文所用术语“治疗”既指治愈或减轻疾病或病症的治疗,又指防止疾病或病症发生的治疗。术语治疗还指CNS或PNS(周围神经***)神经元、少突神经胶质细胞或神经胶质细胞损伤后,通过诱导神经元和/或神经胶质细胞的发生,影响由干细胞或祖细胞的细胞发生,或者指阻止CNS或PNS中生理性年龄相关的衰退,该术语还指培养干细胞或祖细胞并移植入患者CNS或PNS。所述治疗可以急性方式进行或以长期治疗的方式进行。
如上所述,按照本发明使用的药学活性物质适用于治疗影响神经干细胞、祖细胞和/或衍生自神经干细胞或祖细胞的细胞的异常病症。因此该物质可用来预防、治疗或改善中枢神经***(CNS)的损伤、病症或缺陷。按照本发明使用的药学活性物质尤其适合治疗影响少突神经胶质细胞、星形神经胶质细胞和/或神经元细胞的病症。此类病症可以是诸如CNS损伤或缺陷、神经元细胞丧失或记忆丧失。此类病症可由许多不同因子或疾病引起,如多发性硬化症、缺氧性损伤、局部缺血性损伤、创伤性损伤、帕金森氏病及脱髓鞘病。
按照本发明使用的药学活性物质的作用缘于该物质具有诱导中枢神经***中或来自中枢神经***的祖细胞衍生细胞的细胞发生或繁殖和/或分化的能力。
按照本发明的另一个实施方案,可以使用生长激素或其功能相当的类似物以便在组织培养或细胞培养中繁殖祖细胞或干细胞或其它神经细胞。因此这类细胞可用于将细胞移植入罹患神经元细胞丧失或这类内源性细胞缺乏引起的病症。用来开始培养的细胞可来源于患者自身或动物供体。
当需要从患者体内取出细胞进行体外繁殖时,可能最好首先增加患者体内祖细胞的数量。这样有助于随后从患者体内分离所述细胞。使用本发明的方法或药用产品可提高祖细胞的数量,即使用给予患者时使生长激素或其功能相当的类似物浓度增加的物质。
生长激素或其功能相当的类似物可单独使用或与其它药物或设计用于诱导CNS或PNS的细胞发生或细胞增殖的生长因子如表皮生长因子(EGF)或成纤维细胞生长因子2(FGF2)联合使用。生长激素或其功能相当的类似物可单独使用,或与其它药物、肽类、生长因子、类固醇类、脂质、糖基化蛋白或肽类或者同时或依次联合使用,以便促进体外或体内的细胞发生或特殊细胞类型的产生。生长激素或其功能相当的类似物还可用于诱导未成熟细胞或多潜能细胞激活特异性发育程序及前述细胞中的特异性基因。
以上所述细胞发生是指在成人CNS或PNS中或体外从多潜能细胞、祖细胞或干细胞产生诸如神经元少突神经胶质细胞许旺氏细胞及星形神经胶质细胞的新细胞。
此外,本发明还涉及降低患者活性GH或天然GH类似物含量,并因此减少轴索或脊髓损伤患者少突神经胶质细胞的发生的物质的治疗用途。此类物质的实例为负向调节结合蛋白、GH受体拮抗剂、药物或抗体或化合物或肽类。已表明少突神经胶质细胞表达的某些分子抑制轴索再生和脊髓损伤。而且,还可使用增加内源性肽类的药物或抗体或化合物或肽类,或者降低内源性GH生物活性的蛋白质。
如果阅读下列实施例,将对本发明有更全面的了解。但是不应认为这些实施例限制本发明的范畴。
附图简述
以下实施例中,涉及附图,其中:
图1显示与只用氢化可的松(C)和L-甲状腺素(T)处理的垂体切除(Hx)的大鼠及对照组大鼠相比,按照本发明用生长激素(GH)和C以及T处理7天后的垂体切除大鼠齿状回中BrdU-阳性细胞的密度。
图2显示最后一次用BrdU注射垂体切除动物后4周,按照本发明用可的松、甲状腺素和GH处理的动物,比只用可的松和甲状腺素处理的垂体切除动物的粒细胞神经元明显增加。
图3显示,与对照组(●)相比,按照本发明新生细胞数增加的动物(○)在用于测定空间行为的平台隐藏型水迷宫作业中具有明显更好的表现。
实施例
在此实施例中,将按照本发明用生长激素(GH)、氢化可的松(C)和L-甲状腺素(T)处理的垂体切除(Hx)大鼠齿状回中BrdU-阳性细胞的密度,与用氢化可的松(C)和L-甲状腺素(T)处理的垂体切除(Hx)大鼠齿状回中BrdU-阳性细胞的密度以及与未处理未手术的对照组中BrdU-阳性细胞的密度作对比。
完整或50天龄切除垂体的Fisher大鼠(Harlan Sprague Dawley)保持在温度(24-26℃)、湿度(50-60%)及灯光(0500-1900h)的标准条件下。
所述大鼠自由进食标准实验食物和水。垂体切除后7-10天开始进行激素治疗。所有垂体切除大鼠每日均皮下注射(在0800h)给予生理盐水稀释的氢化可的松磷酸盐(400μg/kg/天;Solu-Cortef,Upjohn,Puurs,Belgium)和L-甲状腺素(10μg/kg/天;Sigma,USA)。用pH8.6、含有1.6%甘油和0.02%叠氮化钠的0.05M磷酸盐缓冲液稀释重组牛GH(bGH)。以24小时间隔每日一次皮下注射给予GH 1mg/kg/天。该治疗持续7天。此后处死大鼠并取出脑组织,将其制备用于免疫组化。
10只垂体切除大鼠只用可的松和L-甲状腺素替代。15只垂体切除大鼠用可的松(cortisole)、L-甲状腺素和生长激素替代。将10只120g重的大鼠指定为对照组。在7天的治疗期中,所有动物均每日腹膜内注射溴脱氧尿苷(BrdU;Sigma)(50mg/kg体重)。该胸腺嘧啶核苷类似物BrdU在有丝***时加入遗传物质中,然后在所得细胞中通过免疫组化观察该胸腺嘧啶核苷类似物BrdU。在第20天,通过致死剂量的麻醉剂处死并用4%多聚甲醛经贲门(transcardially)灌注所有动物。取出脑组织并在4%多聚甲醛中后固定24小时,然后在30%蔗糖溶液中贮存。将冠状冷冻切片机切得的切片(40μm)在-20℃下贮存于低温防护剂(25%乙二醇、25%甘油、0.05M磷酸盐缓冲液)中,直到作免疫组化或免疫荧光处理。
使用无***误差的计数技术,计数海马齿状回中的BrdU阳性细胞数。为检测组织切片中BrdU标记的细胞核,在用1∶400的小鼠抗-BrdU抗体(Boeringer Mannheim)温育之前进行如下的DNA变性步骤:于65℃下在50%甲酰胺/2×SSC(0.3M NaCl、0.03M柠檬酸钠)中温育2小时,以2×SSC轻洗5分钟,在2N HCl中于37℃下温育30分钟,在pH8.5的0.1M硼酸中轻洗10分钟。所有染色在自由漂浮的40mm切片上进行。将自由漂浮的切片用溶于tris缓冲盐水(TBS)(0.15M NaCl、0.1M Tris-HCl,pH7.5)的0.6%H2O2处理30分钟以封闭内源性过氧化物酶。在TBS中轻洗几次之后,在TBS/0.25%Triton X-100/3%正常马血清(TBS-TS)中温育30分钟,并于4℃下在TBS-TS中与一抗温育过夜。在TBS-TS中轻洗之后,将切片用生物素化的马抗小鼠IgG、1∶160的二抗(Vector Laboratories,USA)温育3小时。TBS轻洗后涂覆抗生物素蛋白-生物素-过氧化物酶复合物1小时,然后进行5分钟的过氧化物酶检测(0.25mg/ml二氨基联苯胺、0.01%H2O2、0.04%NiCl)。
对于免疫荧光,如上所述处理切片以使DNA变性,接着在TBS-TS中温育30分钟。随后将这些切片于4℃下用1∶2000的小鼠-抗-Calbindin-D28k(Sigma)温育16小时,并用Texas红偶联的驴抗-小鼠IgG检测。用FITC偶联的兔抗-BrdU抗体检测BrdU。使用聚焦扫描激光显微镜(Bio-Rad MRC 1024,Richmond,CA)检测并处理荧光信号。
在包含齿状回的相距240mm的7-9张冠状切片中,检测在粒细胞层、亚粒状细胞层和齿状核门(hilus)及其相应样品体积中的BrdU阳性细胞总数。按照光学解剖器方法进行细胞计数以避免取样误差。
结果见图1。7天后,与只用可的松和甲状腺素替代的动物相比,在用GH、可的松和甲状腺素取代的垂体切除动物齿状回中新生细胞数量明显增加。而且,替代一周后,测得将GH给予氢化可的松和L-甲状腺素处理的垂体切除动物后,细胞增殖速率显著增加。这些结果清楚地表明GH提高了海马齿状回祖细胞的增殖速率。
此外,替代一周后,测得将GH给予氢化可的松和L-甲状腺素处理的垂体切除动物后,细胞增殖速率显著增加。这一结果提示GH影响海马齿状回祖细胞的增殖速率。
而且,与正常对照及与替代一周并在此后的3周未替代的垂体切除动物相比,用GH处理一周的正常动物的细胞增殖增加。用可的松和L-甲状腺素或者用可的松、L-甲状腺素和GH处理后一个月,评估BrdU阳性细胞数,结果见表2。
该结果提示GH或者直接或者间接促进齿状回中神经细胞祖细胞增殖所产生的细胞的增殖或存活。
本发明的发明者首次表明生长激素能调节成年动物脑神经元的增殖及随后的增殖。
注射BrdU之后4周,连续4天检测并比较新生细胞数增加的大鼠与新生细胞数较少的大鼠。用录像跟踪***在水迷宫中检测大鼠。监测到达平台的时间(潜隐期,latency)。救生平台(escape platform)隐藏在水面下1cm处的固定位置。通过在水中加入干奶粉使之不透明。在整个实验期间水温保持恒定的22℃。每天检测每只动物4次。每次试验持续45秒。将未能在45秒内发现隐藏平台的动物潜隐期指定为45秒,并放置于平台上,允许在平台停留15秒。
用双因素方差分析在水迷宫检测期间发现平台的潜隐期,并使用Scheffe F-检验对每次监测的间隔时间进行重复性后比较检验(repeatedpostcomparative test)。结果见图3。各小鼠在游泳速度上没有显著差别。显然由于按照本发明处理而齿状回新生细胞数量增多的动物,在空间感知任务中明显完成得比较好。这些动物组的数据在图中以○表示。新生细胞数较低大鼠的数据在图中以●表示。
Claims (34)
1.一种物质用于生产治疗影响神经干细胞、祖细胞和/或衍生自神经干细胞或祖细胞的细胞的病症的药用产品的用途,其中所述物质给予患者时使生长激素或其功能相当的类似物浓度增加。
2.按照权利要求1的用途,其中所述物质为生长激素或其功能相当的类似物。
3.按照权利要求1的用途,其中给予所述物质将增加内源性生长激素的释放。
4.按照权利要求1-3任意一项的用途,其中所述病症影响少突神经胶质细胞、星形神经胶质细胞和/或神经元细胞。
5.按照权利要求1-4任意一项的用途,其中所述病症影响非胆碱能神经元细胞、胆碱能神经元细胞或神经胶质细胞。
6.按照权利要求1-5任意一项的用途,其中所述病症为CNS损伤或缺陷。
7.按照权利要求1-6任意一项的用途,其中所述病症为神经细胞丧失。
8.按照权利要求1-7任意一项的用途,其中所述病症为记忆丧失。
9.按照权利要求1-8任意一项的用途,其中所述病症由多发性硬化症、缺氧性损伤、局部缺血性损伤、创伤性损伤、帕金森氏病和/或脱髓鞘病引起。
10.按照权利要求1-9任意一项的用途,其中所述药用产品配制用于静脉输注、肌肉注射或皮下注射。
11.按照权利要求1-10任意一项的用途,其中配制所述药用产品以便当将所述药用产品给予患者时,所述活性物质将进入所述患者脑室中。
12.按照权利要求1-11任意一项的用途,其中配制所述药用产品以便当将所述药用产品给予患者时,所述活性物质将进入所述患者脑脊液中。
13.一种物质用于生产治疗影响中枢神经***的病症的药用产品的用途,其中所述物质给予患者时使生长激素或其功能相当的类似物浓度降低。
14.按照权利要求13的用途,其中所述物质为负向调节生长激素结合蛋白、其功能相当的类似物、抗生长激素的抗体、生物活性生长激素受体抑制剂和/或内源性生长激素释放的抑制剂。
15.按照权利要求13或14的用途,其中所述病症为由以下原因所致:震荡所致的轴索损伤、头部创伤所致的轴索损伤、CNS小血管病所致的轴索损伤、疾病和/或创伤对脊髓的损伤。
16.一种方法,该方法通过给予体外干细胞、祖细胞、神经元星形神经胶质细胞和/或少突神经胶质细胞有效量的生长激素或其功能相当的类似物,从而诱导谱系定向(lineage determination)、繁殖和/或诱导或保持由祖细胞、干细胞和/或衍生自所述细胞的细胞产生神经元、少突神经胶质细胞、星形神经胶质细胞。
17.一种方法,该方法诱导谱系定向、或者诱导或保持由患者中枢或外周神经***中的祖细胞或干细胞或衍生自患者中枢或外周神经***的祖细胞或干细胞产生神经元、少突神经胶质细胞、星形神经胶质细胞,其中给予所述患者药学有效量的使生长激素或其功能相当的类似物浓度增加的物质。
18.按照权利要求17的方法,其中所述物质为生长激素或其功能相当的类似物。
19.按照权利要求17的方法,其中所述物质为使内源性生长激素释放增加的物质。
20.按照权利要求17的方法,用于治疗影响患者神经***的病症。
21.按照权利要求20的方法,其中所述病症影响少突神经胶质细胞、星形神经胶质细胞和/或神经元细胞。
22.按照权利要求22的方法,其中所述病症影响非胆碱能神经元细胞、胆碱能神经元细胞或神经胶质细胞。
23.按照权利要求20的方法,其中所述病症为CNS损伤或缺陷。
24.按照权利要求23的方法,其中所述病症为神经细胞丧失。
25.按照权利要求23的方法,其中所述病症为记忆丧失。
26.按照权利要求23的方法,其中所述病症由至少一种源自多发性硬化症、缺氧性损伤、局部缺血性损伤、创伤性损伤、帕金森氏病和脱髓鞘病的因素引起。
27.按照权利要求17的方法,其中通过静脉内输注、肌肉注射或皮下注射给予所述物质。
28.按照权利要求17的方法,其中所述给药后从所述患者取出脑细胞,然后将所述脑细胞在体外增殖,接着将所获得的细胞移植回所述患者脑中。
29.按照权利要求28的方法,其中在所述脑细胞体外增殖期间给予其有效量的生长激素或其功能相当的类似物。
30.一种方法,该方法减少由患者中枢或外周神经***中的祖细胞或干细胞或者衍生自患者中枢或外周神经***的祖细胞或干细胞产生少突神经胶质细胞、神经元、星形神经胶质细胞,其中给予所述患者药学有效量的使生长激素或其功能相当的类似物浓度下降的物质。
31.按照权利要求30的方法,其中将所述物质给予到所述患者的外周或中枢神经***。
32.按照权利要求30的方法,其中所述物质选自负向调节生长激素的结合蛋白、其功能相当的类似物、抗生长激素的抗体、生物活性的生长激素受体抑制剂以及内源性GH释放抑制剂。
33.按照权利要求30的方法,用于治疗中枢神经***损伤。
34.按照权利要求33的方法,其中所述损伤为由源自以下的一种因素所致:震荡所致的轴索损伤、头部创伤所致的轴索损伤、CNS小血管病所致的轴索损伤、疾病或创伤后对脊髓的损伤。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE9804064A SE9804064D0 (sv) | 1998-11-25 | 1998-11-25 | Medicinal product and method for treatment of conditions affecting neural stem cells or progenitor cells |
SE98040645 | 1998-11-25 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1333691A true CN1333691A (zh) | 2002-01-30 |
Family
ID=20413429
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN99815708A Pending CN1333691A (zh) | 1998-11-25 | 1999-11-25 | 用于治疗影响神经干细胞或祖细胞的病症的药用产品及方法 |
Country Status (11)
Country | Link |
---|---|
US (2) | US6797264B1 (zh) |
EP (1) | EP1135156A2 (zh) |
JP (1) | JP2002530351A (zh) |
CN (1) | CN1333691A (zh) |
AU (1) | AU772340B2 (zh) |
CA (1) | CA2352553A1 (zh) |
IL (1) | IL143283A0 (zh) |
NZ (1) | NZ512495A (zh) |
SE (1) | SE9804064D0 (zh) |
WO (1) | WO2000030675A2 (zh) |
ZA (1) | ZA200104093B (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107019800A (zh) * | 2012-02-15 | 2017-08-08 | 纽洛可科学有限公司 | 参与调节胶质细胞生成的fam19a5的医药用途 |
CN107980095A (zh) * | 2015-05-10 | 2018-05-01 | 文塔纳医疗***公司 | 用于在自动化多重组织组织染色测定期间使碱性磷酸酶和过氧化物酶同时失活的组合物和方法 |
Families Citing this family (34)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1016413A1 (en) * | 1998-12-30 | 2000-07-05 | Applied Research Systems ARS Holding N.V. | Human growth hormone to stimulate mobilization of pluripotent hematopoietic stem cells |
AR036400A1 (es) * | 2001-08-30 | 2004-09-08 | Stem Cell Therapeutics Inc | Regulacion combinada de la produccion de celulas nerviosas. |
WO2003024472A2 (en) * | 2001-09-14 | 2003-03-27 | Stem Cell Therapeutics Inc. | Prolactin induced increase in neutral stem cell numbers and therapeutical use thereof |
WO2003024471A2 (en) * | 2001-09-18 | 2003-03-27 | Stem Cell Therapeutics Inc. | Effect of growth hormone and igf-1 on neural stem cells and therapeutic application |
CA2492442A1 (en) | 2002-07-31 | 2004-02-05 | Stem Cell Therapeutics Inc. | Method of enhancing neural stem cell proliferation, differentiation, and survival using pituitary adenylate cyclase activating polypeptide (pacap) |
AU2005211847B2 (en) | 2004-02-13 | 2011-02-24 | Stem Cell Therapeutics Corp. | Use of luteinizing hormone (LH) and chorionic gonadotropin (hCG) for proliferation of neural stem cells and neurogenesis |
CU23529A1 (es) * | 2005-03-02 | 2010-06-17 | Ct Ingenieria Genetica Biotech | Combinación de egf/ghrp-6 para la neuroregeneración del sistema nervioso central posterior al dano autoinmune |
EP2275095A3 (en) | 2005-08-26 | 2011-08-17 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation |
EP2258358A3 (en) | 2005-08-26 | 2011-09-07 | Braincells, Inc. | Neurogenesis with acetylcholinesterase inhibitor |
KR20080074108A (ko) | 2005-09-27 | 2008-08-12 | 스템 셀 테라퓨틱스 코포레이션 | 프로락틴에 의해 조절되는 올리고덴드로사이트 전구체 세포증식 |
JP2009512711A (ja) | 2005-10-21 | 2009-03-26 | ブレインセルス,インコーポレイティド | Pde阻害による神経新生の調節 |
CA2625210A1 (en) | 2005-10-31 | 2007-05-10 | Braincells, Inc. | Gaba receptor mediated modulation of neurogenesis |
US20070244143A1 (en) * | 2006-03-08 | 2007-10-18 | Braincells, Inc | Modulation of neurogenesis by nootropic agents |
US20100216734A1 (en) * | 2006-03-08 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis by nootropic agents |
KR20080106976A (ko) * | 2006-03-17 | 2008-12-09 | 스템 셀 테라퓨틱스 코포레이션 | 신경 줄기 세포 증식제 및 신경 줄기 세포 분화제의 연속 투여 방법 |
US20090197823A1 (en) * | 2006-05-09 | 2009-08-06 | Braincells, Inc. | Aliskiren modulation of neurogenesis |
AU2007249399A1 (en) | 2006-05-09 | 2007-11-22 | Braincells, Inc. | Neurogenesis by modulating angiotensin |
JP2009536667A (ja) * | 2006-05-09 | 2009-10-15 | ブレインセルス,インコーポレイティド | 5ht受容体介在性の神経新生 |
US20100009983A1 (en) * | 2006-05-09 | 2010-01-14 | Braincells, Inc. | 5 ht receptor mediated neurogenesis |
KR20090064418A (ko) * | 2006-09-08 | 2009-06-18 | 브레인셀즈 인코퍼레이션 | 4-아실아미노피리딘 유도체 포함 조합물 |
US20100184806A1 (en) | 2006-09-19 | 2010-07-22 | Braincells, Inc. | Modulation of neurogenesis by ppar agents |
WO2008036678A2 (en) * | 2006-09-19 | 2008-03-27 | Braincells, Inc. | Combination comprising a peroxisome proliferator activated receptor agent and a second neurogenic agent for treating a nervous system disorder, increasing neurodifferentiation and increasing neurogenesis |
CU23526B6 (es) | 2006-10-03 | 2010-05-19 | Ct Ingenieria Genetica Biotech | Método para la restauración morfofuncional de nervios periféricos en la neuropatía diabética |
WO2008083204A2 (en) * | 2006-12-28 | 2008-07-10 | Braincells, Inc. | Modulation of neurogenesis by melatoninergic ligands |
EP2125017A2 (en) * | 2007-01-11 | 2009-12-02 | Braincells, Inc. | Modulation of neurogenesis with use of modafinil |
WO2008097861A2 (en) * | 2007-02-02 | 2008-08-14 | Braincells, Inc. | MODULATION OF NEUROGENESIS WITH BIGUANIDES AND GSK3-ß AGENTS |
WO2009111778A2 (en) | 2008-03-07 | 2009-09-11 | University Of Pittsburgh-Of The Commonwealth System Of Higher Education | Lymph nodes as a site for regeneration |
WO2014138486A1 (en) * | 2013-03-06 | 2014-09-12 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Lymph node as a site for transplantation, organogenesis and function for multiple tissues and organs |
US20090239834A1 (en) * | 2008-03-21 | 2009-09-24 | Braincells, Inc. | Mcc-257 modulation of neurogenesis |
WO2010099217A1 (en) | 2009-02-25 | 2010-09-02 | Braincells, Inc. | Modulation of neurogenesis using d-cycloserine combinations |
ES2702461T3 (es) | 2009-03-20 | 2019-03-01 | Hg&H Pharmaceuticals Pty Ltd | Extracto de Sceletium y usos del mismo |
PL2408446T3 (pl) | 2009-03-20 | 2020-03-31 | Hg&H Pharmaceuticals (Pty) Limited | Zastosowanie kompozycji farmaceutycznych zawierających mesembrenon |
EP2751095B1 (en) | 2011-08-29 | 2021-10-27 | Sanford-Burnham Medical Research Institute | Novel benzodiazepinones as modulators of metabotropic glutamate receptor functions and neurological uses thereof |
CN108904779B (zh) * | 2018-09-29 | 2019-12-03 | 南华大学 | 曲普瑞林的新应用 |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8625941D0 (en) * | 1986-10-30 | 1986-12-03 | Sandoz Ltd | Substituted alpha-amino acids |
US4871717A (en) | 1987-01-07 | 1989-10-03 | Administrators Of The Tulane Educational Fund | Peptides |
ES2109914T3 (es) * | 1988-01-11 | 1998-02-01 | Chaovanee Aroonsakul | Utilizacion de hormonas anabolicas para la fabricacion de una medicina para el tratamiento de la demencia senil y la enfermedad de alzheimer. |
US5650148A (en) * | 1988-12-15 | 1997-07-22 | The Regents Of The University Of California | Method of grafting genetically modified cells to treat defects, disease or damage of the central nervous system |
JP2882679B2 (ja) | 1989-04-26 | 1999-04-12 | ジ・アドミニストレーターズ・オブ・ザ・ツーレイン・エデュケイショナル・ファンド | 線状ソマトスタチン類似体 |
AU8864691A (en) | 1990-09-07 | 1992-03-30 | Regents Of The University Of California, The | Glial antiproliferative proteins |
US5980885A (en) * | 1991-07-08 | 1999-11-09 | Neurospheres Holdings Ltd. | Growth factor-induced proliferation of neural precursor cells in vivo |
US5750376A (en) * | 1991-07-08 | 1998-05-12 | Neurospheres Holdings Ltd. | In vitro growth and proliferation of genetically modified multipotent neural stem cells and their progeny |
US5851832A (en) * | 1991-07-08 | 1998-12-22 | Neurospheres, Ltd. | In vitro growth and proliferation of multipotent neural stem cells and their progeny |
DE69334344D1 (de) * | 1992-10-28 | 2010-11-18 | Neurospheres Holding Ltd | Biologische Faktoren und neuronale Stammzellen |
WO1994022469A1 (en) * | 1993-04-02 | 1994-10-13 | Ohio University | Enhancement of learning and/or memory by a human somatotropin |
JPH10509592A (ja) | 1994-11-14 | 1998-09-22 | ニューロスフィアーズ ホウルディングス リミテッド | 神経幹細胞増殖調節 |
US6284539B1 (en) * | 1998-10-09 | 2001-09-04 | Neuralstem Biopharmaceuticals, Ltd. | Method for generating dopaminergic cells derived from neural precursors |
-
1998
- 1998-11-25 SE SE9804064A patent/SE9804064D0/xx unknown
-
1999
- 1999-11-25 NZ NZ512495A patent/NZ512495A/en not_active IP Right Cessation
- 1999-11-25 CA CA002352553A patent/CA2352553A1/en not_active Abandoned
- 1999-11-25 AU AU20138/00A patent/AU772340B2/en not_active Ceased
- 1999-11-25 IL IL14328399A patent/IL143283A0/xx unknown
- 1999-11-25 CN CN99815708A patent/CN1333691A/zh active Pending
- 1999-11-25 US US09/856,576 patent/US6797264B1/en not_active Expired - Fee Related
- 1999-11-25 EP EP99963765A patent/EP1135156A2/en not_active Withdrawn
- 1999-11-25 WO PCT/SE1999/002197 patent/WO2000030675A2/en not_active Application Discontinuation
- 1999-11-25 JP JP2000583558A patent/JP2002530351A/ja active Pending
-
2001
- 2001-05-18 ZA ZA200104093A patent/ZA200104093B/en unknown
-
2004
- 2004-09-03 US US10/933,516 patent/US20050032702A1/en not_active Abandoned
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107019800A (zh) * | 2012-02-15 | 2017-08-08 | 纽洛可科学有限公司 | 参与调节胶质细胞生成的fam19a5的医药用途 |
US11739141B2 (en) | 2012-02-15 | 2023-08-29 | Neuracle Science Co., Ltd. | Pharmaceutical use of FAM19A5 involved in regulating gliogenesis |
CN107980095A (zh) * | 2015-05-10 | 2018-05-01 | 文塔纳医疗***公司 | 用于在自动化多重组织组织染色测定期间使碱性磷酸酶和过氧化物酶同时失活的组合物和方法 |
US11162877B2 (en) | 2015-05-10 | 2021-11-02 | Ventana Medical Systems, Inc. | Compositions and methods for simultaneous inactivation of alkaline phosphatase and peroxidase enzymes during automated multiplex tissue staining assays |
US11971337B2 (en) | 2015-05-10 | 2024-04-30 | Ventana Medical Systems, Inc. | Compositions and methods for simultaneous inactivation of alkaline phosphatase and peroxidase enzymes during automated multiplex tissue staining assays |
Also Published As
Publication number | Publication date |
---|---|
WO2000030675A2 (en) | 2000-06-02 |
ZA200104093B (en) | 2003-08-18 |
US20050032702A1 (en) | 2005-02-10 |
NZ512495A (en) | 2003-10-31 |
US6797264B1 (en) | 2004-09-28 |
CA2352553A1 (en) | 2000-06-02 |
IL143283A0 (en) | 2002-04-21 |
JP2002530351A (ja) | 2002-09-17 |
AU772340B2 (en) | 2004-04-22 |
AU2013800A (en) | 2000-06-13 |
SE9804064D0 (sv) | 1998-11-25 |
EP1135156A2 (en) | 2001-09-26 |
WO2000030675A3 (en) | 2000-08-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1333691A (zh) | 用于治疗影响神经干细胞或祖细胞的病症的药用产品及方法 | |
Alcantara et al. | TrkB signaling is required for postnatal survival of CNS neurons and protects hippocampal and motor neurons from axotomy-induced cell death | |
Richardson et al. | Regeneration and retrograde degeneration of axons in the rat optic nerve | |
US7214372B2 (en) | Methods using lineage restricted glial precursors from the central nervous system | |
Van Den Pol et al. | Olfactory ensheathing cells: time lapse imaging of cellular interactions, axonal support, rapid morphologic shifts, and mitosis | |
Blaker et al. | Cholinergic neurons within the rat hippocampus: Response to fimbria‐fornix transection | |
CN1170434A (zh) | 体外诱导多巴胺能的细胞 | |
IE911460A1 (en) | Human neuronal cell line | |
Grothe et al. | Neuron‐enriched cultures of adult rat dorsal root ganglia: Establishment, characterization, survival, and neuropeptide expression in response to trophic factors | |
CA2095300C (en) | Use of genetically modified cells to treat defects, disease or damage of the central nervous system | |
Martinez‐Serrano et al. | Ex vivo gene transfer of brain‐derived neurotrophic factor to the intact rat forebrain: neurotrophic effects on cholinergic neurons | |
AU770501B2 (en) | Ependymal neural stem cells and method for their isolation | |
Harkany et al. | Redistribution of CB1 cannabinoid receptors during evolution of cholinergic basal forebrain territories and their cortical projection areas: a comparison between the gray mouse lemur (Microcebus murinus, primates) and rat | |
Attar et al. | Electron microscopic study of the progeny of ependymal stem cells in the normal and injured spinal cord | |
Avendaño et al. | Decrease and long‐term recovery of choline acetyltransferase immunoreactivity in adult cat somatosensory cortex after peripheral nerve transections | |
Li et al. | Development of calcitonin‐gene‐related peptide, chromogranin a, and synaptic vesicle markers in rat motor endplates, studied using immunofluorescence and confocal laser scanning | |
Leibowitz et al. | Sustained somatostatin gene expression reverses kindling-induced increases in the number of dividing Type-1 neural stem cells in the hippocampi of behaviorally responsive rats | |
Cho et al. | Immunocytochemical study with an anti-transferrin binding protein serum: a marker for avian oligodendrocytes | |
Barone Jr et al. | The effects of NGF and fetal cell transplants on spatial learning after intradentate administration of colchicine | |
Deng et al. | GDNF reverses the inhibitory properties of reactive astrocytes allowing robust axonal regeneration through Schwann cell-seeded guidance channels after spinal cord injury | |
CN113880912B (zh) | 一种短肽及其在癫痫治疗中的应用 | |
Gray | Cell lineage in the chicken optic tectum: Clonal analysis of migratory paths and phenotypic choices | |
JPH0928378A (ja) | 神経細胞特異的に発現するアデノウイルスベクター | |
Wiencken-Barger | The roles of* L1 and NCAM in brain development | |
Sawamoto et al. | Arantxa Cebrián-Silla, Clara Alfaro-Cervelló, 2 Vicente Herranz-Pérez, Naoko Kaneko, 4 Dae Hwi Park, 5 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
C10 | Entry into substantive examination | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
ASS | Succession or assignment of patent right |
Owner name: CELL TREATMENT SCANDINAVIA CO., LTD. Free format text: FORMER OWNER: A+ SCIENCE STOCK CO., LTD. Effective date: 20030327 |
|
C41 | Transfer of patent application or patent right or utility model | ||
TA01 | Transfer of patent application right |
Effective date of registration: 20030327 Address after: Gothenburg Applicant after: Cell therapy, Scandinavia, Limited by Share Ltd Address before: Gothenburg Applicant before: A+ science, Limited by Share Ltd |
|
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |