JP5897335B2 - 改良された細胞株及びカプセル化細胞生体送達におけるその使用 - Google Patents
改良された細胞株及びカプセル化細胞生体送達におけるその使用 Download PDFInfo
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- 229960004666 glucagon Drugs 0.000 description 1
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- 229940049906 glutamate Drugs 0.000 description 1
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- 238000003306 harvesting Methods 0.000 description 1
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- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 229940124589 immunosuppressive drug Drugs 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000001153 interneuron Anatomy 0.000 description 1
- 230000006662 intracellular pathway Effects 0.000 description 1
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002605 large molecules Chemical class 0.000 description 1
- 238000001638 lipofection Methods 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 210000005171 mammalian brain Anatomy 0.000 description 1
- 102000016470 mariner transposase Human genes 0.000 description 1
- 108060004631 mariner transposase Proteins 0.000 description 1
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 1
- 210000002901 mesenchymal stem cell Anatomy 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
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- 229960002748 norepinephrine Drugs 0.000 description 1
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- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 210000004248 oligodendroglia Anatomy 0.000 description 1
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- 239000002245 particle Substances 0.000 description 1
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- DULMZMHLQQZGPY-ACFXXXONSA-N peptite 2000 Chemical compound NC(=N)NCCC[C@@H](C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)CNC(=O)CNC(=O)CNC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CCCNC(N)=N)NC(=O)CNC(C)=O DULMZMHLQQZGPY-ACFXXXONSA-N 0.000 description 1
- 208000028591 pheochromocytoma Diseases 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 210000001778 pluripotent stem cell Anatomy 0.000 description 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 1
- 229920002627 poly(phosphazenes) Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 229920002959 polymer blend Polymers 0.000 description 1
- 108010055896 polyornithine Proteins 0.000 description 1
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- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920000131 polyvinylidene Polymers 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 230000001323 posttranslational effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229940048914 protamine Drugs 0.000 description 1
- 239000000007 protein synthesis inhibitor Substances 0.000 description 1
- XNSAINXGIQZQOO-SRVKXCTJSA-N protirelin Chemical compound NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H]1NC(=O)CC1)CC1=CN=CN1 XNSAINXGIQZQOO-SRVKXCTJSA-N 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 239000000790 retinal pigment Substances 0.000 description 1
- 230000017248 retroviral genome replication Effects 0.000 description 1
- 238000009781 safety test method Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- LIVNPJMFVYWSIS-UHFFFAOYSA-N silicon monoxide Chemical class [Si-]#[O+] LIVNPJMFVYWSIS-UHFFFAOYSA-N 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 229960000553 somatostatin Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 229940063673 spermidine Drugs 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
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- 230000035882 stress Effects 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003356 suture material Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 108060008037 tachykinin Proteins 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 229940034199 thyrotropin-releasing hormone Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 230000005026 transcription initiation Effects 0.000 description 1
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- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
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- 210000004127 vitreous body Anatomy 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000009941 weaving Methods 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
-
- 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
- A61K38/18—Growth factors; Growth regulators
- A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
- C12N15/88—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation using microencapsulation, e.g. using amphiphile liposome vesicle
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
- C12N15/90—Stable introduction of foreign DNA into chromosome
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
- C12N15/90—Stable introduction of foreign DNA into chromosome
- C12N15/902—Stable introduction of foreign DNA into chromosome using homologous recombination
- C12N15/907—Stable introduction of foreign DNA into chromosome using homologous recombination in mammalian cells
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K2035/126—Immunoprotecting barriers, e.g. jackets, diffusion chambers
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2800/00—Nucleic acids vectors
- C12N2800/90—Vectors containing a transposable element
Description
a. 生体適合性を有する外膜及び内部コアを備え、
b. 前記内部コアは、細胞を含み
c. 前記細胞は、構造遺伝子を有する異種発現コンストラクト(heterologous expression construct)を含み、前記構造遺伝子は、
i. 分泌生物活性ポリペプチドをコードするか、或いは、
ii. 生物活性を有する分泌化合物の細胞における生成に寄与するポリペプチド又はsiRNAをコードし、
d. 前記遺伝子は、トランスポザーゼ又は他のインテグラーゼの基質である2つの逆方向反復間に位置する。
i. 分泌生物活性ポリペプチドをコードするか、或いは、
ii. 生物活性を有する分泌化合物の細胞における生成に寄与するポリペプチド又はsiRNAをコードし、
前記遺伝子は、トランスポザーゼの基質である2つの逆方向反復間に位置する。
a. 第1及び第2の発現コンストラクトにより細胞をトランスフェクトするステップと、
b. 前記第1の発現コンストラクトは、トランスポザーゼをコードする読み取り枠を含むことと、
c. 前記第2の発現コンストラクトは、分泌生物活性ポリペプチドをコードするか、或いは、生物活性を有する分泌化合物の細胞における生成に寄与するポリペプチド又はsiRNAをコードすることと、
d. 前記第2の発現コンストラクトは、前記トランスポザーゼの基質である2つの逆方向反復間に位置することと、
e. 前記トランスポザーゼの一時的発現を発生させ、これにより、ヒト細胞のゲノムへの前記第2の発現コンストラクトの組み込みを発生させるステップと、を備える方法に関する。
- K14R;
- K13D;
- K13A;
- K30R;
- K33A;
- T83A;
- I100L;
- R115H;
- R143L;
- R147E;
- A205K/H207V/K208R/D210E;
- H207V/K208R/D210E;
- R214D/K215A/E216V/N217Q;
- M243H;
- M243Q;
- E267D;
- T314N; 及び
- G317E。
- 変異体 1: K14R//R214D/K215A/E216V/N217Q;
- 変異体 2: K33A/R1 15H//R214D/K215A/E216V/N217Q//M243H;
- 変異体 3:
K14R/K30R//A205K/H207V/K208R/D210E//R214D/K215A/E216V/N217Q//M243H;
- 変異体 4: K13D/K33A/T83A//H207V/K208R/D210E//M243Q;
- 変異体 5: K13A/K33A//R214D/K215A/E216V/N217Q;
- 変異体 6: K33A/T83A//R214D/K215A/E216V/N217Q//G317E;
- 変異体 7: K14R/T83A/M243Q;
- 変異体 8: K14R/T83A/I100L/M243Q;
- 変異体 9: K14R/T83A/R143L/M243Q;
- 変異体 10: K14R/T83A/R147E/M243Q;
- 変異体 11 : K14R/T83A/M243Q/E267D;
- 変異体 12: K14R/T83A/M243Q/T314N;
- 変異体 13:
K14R/K30R/I100I7/A205K/H207V/K208R/D210E//R214D/K215A/E216V/N217Q//M243H;
- 変異体 14:
K14R/K30R/R143L//A205K/H207V/K208R/D210E//R214D/K215A/E216V/N217Q//M243H;
- 変異体 15:
K14R/K30R/R147E//A205K/H207V/K208R/D210E//R214D/K215A/E216V/N217Q//M243H;
- 変異体 16:
K14R/K30R//A205K/H207V/K208R/D210E//R214D/K215A/E216V/N217Q//M243H/E267D;
- 変異体 17:
K14R/K30R/A205K/H207V/K208R/D210E//R214D/K215A/E216V/N217Q//M243H/T314N;
- 変異体 18:
K14R/K30R//A205K/H207V/K208R/D210E//R214D/K215A/E216V/N217Q//M243H/G317E;
- 変異体 19: K14R/K33A/R115H//R214D/K215A/E216V/N217Q//M243H;
- 変異体 20:
K14R/K30R/R147E//A205K/H207V/K208R/D210E//R214D/K215A/E216V/N217Q//M243H/T314N;
- 変異体 21 :
K14R/K30R/R143L//A205K/H207V/K208R/D210E//R214D/K215A/E216V/N217Q//M243H/E267D;
- 変異体 22:
K14R/K30R/R143I7/A205K/H207V/K208R/D210E//R214D/K215A/E216V/N217Q//M243H/T314N;
- 変異体 23:
K14R/K30R/R143I7/A205K/H207V/K208R/D210E//R214D/K215A/E216V/N217Q//M243H/G317E;
- 変異体 24: K14R/K33A/R115H/R143L//R214D/K215A/E216V/N217Q//M243H;
- 変異体 25: K14R/K33A/R115H/R147E//R214D/K215A/E216V/N217Q//M243H;
- 変異体 26: K14R/K33A/R115H//R214D/K215A/E216V/N217Q//M243H/E267D;
- 変異体 27: K14R/K33A/R1 15H//R214D/K215A/E216V/N217Q//M243H/T314N;
- 変異体 28: K14R/K33A/R115H//R214D/K215A/E216V/N217Q//M243H/G317E;
- 変異体 29: K14R/T83A/M243Q/G317E;
- 変異体 30: K13A/K33A/T83A//R214D/K215A/E216V/N217Q
- 変異体 1: K14R/R214D//K215A/E216V/N217Q;
- 変異体 2: K33A/R115H//R214D/K215A/E216V/N217Q//M243H;
- 変異体 3:
K14R/K30R//A205K/H207V/K208R/D210E//R214D/K215A/E216V/N217Q//M243H;
- 変異体 4: K13D/K33A/T83A//H207V/K208R/D210E//M243Q;
- 変異体 5: K13A/K33A//R214D/K215A/E216V/N217Q;
- 変異体 6: K33A/T83A//R214D/K215A/E216V/N217Q//G317E;
- 変異体 7: K14R/T83A/M243Q;
- 変異体 8: K14R/T83A/l100L7M243Q;
- 変異体 9: K14R/T83A/R143L/M243Q;
- 変異体 10: Kl 4R/T83 A/R147E/M243Q;
- 変異体 11 : K14R/T83A/M243Q/E267D;
- 変異体 12: K14R/T83A/M243Q/T314N;
- 変異体 14:
K14R/K30R/R143I7/A205K/H207V/K208R/D210E//R214D/K215A/E216/N217Q//M243H;
- 変異体 15:
K14R/K30R/R147E//A205K/H207V/K208R/D210E//R214D/K215A/E216V/N217Q//M243H;
- 変異体 16:
K14R/K30R//A205K/H207V/K208R/D210E//R214D/K215A/E216V/N217Q//M243H/E267D;
- 変異体 17:
K14R/K30R//A205K/H207V/K208R/D210E//R214D/K215A/E216V/N217Q//M243H/T314N;
- 変異体 18:
K14R/K30R//A205K/H207V/K208R/D210E//R214D/K215A/E216V/N217Q//M243H/G317E;
- 変異体 19: K14R/K33A/R115H//R214D/K215A/E216V/N217Q//M243H;
- 変異体 20:
K14R/K30R/R147E//A205K/H207V/K208R/D210E//R214D/K215A/E216V/N217Q//M243H/T314N;
- 変異体 21:
K14R/K30R/R143L//A205K/H207V/K208R/D210E//R214D/K215A/E216V/N217Q//M243H/E267D;
- 変異体 23:
K14R/K30R/R14317/A205K/H207V/K208R/D210E//R214D/K215A/E216V/N217Q//M243 H/G317E;
- 変異体 24: K14R/K33A/R1 15H/R143L//R214D/K215A/E216V/N217Q//M243H;
- 変異体 25: K14R/K33A/R115H/R147E//R214D/K215A/E216V/N217Q//M243H;
- 変異体 26: K14R/K33A/R115H//R214D/K215A/E216V/N217Q//M243H/E267D;
- 変異体 27: K14R/K33A/R115H//R214D/K215A/E216V/N217Q//M243H/T314N;
- 変異体 28: K14R/K33A/R115H//R214D/K215A/E216V/N217Q//M243H/G317E;
- 変異体 2: K33A/R115H//R214D/K215A/E216V/N217Q//M243H;
- 変異体 3:
K14R/K30R//A205K/H207V/K208R/D210E//R214D/K215A/E216V/N217Q//M243H;
- 変異体 14:
K14R/K30R/R143IJ/A205K/H207V/K208R/D210E//R214D/K215A/E216V/N217Q//M243H;
- 変異体 15:
K14R/K30R/R147E//A205K/H207V/K208R/D210E//R214D/K215A/E216V/N217Q//M243H;
- 変異体 16:
K14R/K30R//A205K/H207V/K208R/D210E//R214D/K215A/E216V/N217Q//M243H/E267D;
- 変異体 19: K14R/K33A/R115H//R214D/K215A/E216V/N217Q//M243H;
- 変異体 20:
K14R/K30R/R147E//A205K/H207V/K208R/D210E//R214D/K215A/E216V/N217Q//M243HAT314N;
- 変異体 21:
K14R/K30R/R143L7/A205K/H207V/K208R/D210E//R214D/K215A/E216V/N217Q//M243H/E267D;
- 変異体 23:
K14R/K30R/R143L//A205K/H207V/K208R/D210E//R214D/K215A/E216V/N217Q//M243H/G317E;
- 変異体 24: K14R/K33A/R115H/R143L//R214D/K215A/E216V/N217Q//M243H;
- 変異体 25: K14R/K33A/R1 15H/R147E//R214D/K215A/E216V/N217Q//M243H;
- 変異体 26: K14R/K33A/R1 15H//R214D/K215A/E216V/N217Q//M243H/ E267D;
- 変異体 27: K14R/K33A/R115H//R214D/K215A/E216V/N217Q//M243H/T314N;
- 変異体 28: K14R/K33A/R115H//R214D/K215A/E216V/N217Q//M243H/G317E.
Claims (71)
- 分泌生物活性化合物を被験者へ送達するためのカプセルであって、
a. 生体適合性を有する外膜及び内部コアを備え、
b. 当該内部コアは、ヒト単クローン接触抑制性細胞を含み、
当該細胞は、構造遺伝子を有する異種発現コンストラクトを含み、当該構造遺伝子は、
i. 分泌生物活性ポリペプチドをコードするか、或いは、
ii. 生物活性を有する分泌化合物の細胞内での生成に寄与するポリペプチド又はsiRNAをコードし、
当該遺伝子は、Sleeping Beautyトランスポザーゼの基質である2つの逆方向反復間に位置し、かつ、
当該異種発現コンストラクトはSleeping Beautyトランスポザーゼを使用して当該細胞のゲノムに挿入されている、カプセル。 - 前記生体適合性を有する外膜が、前記化合物を通過させる半透性膜である、請求項1に記載のカプセル。
- 前記内部コアがマトリクスを含む、請求項1又は2に記載のカプセル。
- 前記カプセルが1μL未満のカプセル容積を有するマイクロカプセルである、請求項1乃至3の何れかに記載のカプセル。
- 前記カプセルが1乃至10μLのカプセル容積を有するマクロカプセルである、請求項1又は2記載のカプセル。
- カプセル容積1μL当たり10,000乃至250,000細胞を含む、請求項1乃至5の何れかに記載のカプセル。
- 前記カプセルの容積が、0.5乃至10μLの範囲である、請求項1乃至3の何れかに記載のカプセル。
- 1カプセル当たり104未満の細胞を収容する、請求項1乃至7の何れかに記載のカプセル。
- 厚さが最大1000μmである、請求項1乃至8の何れかに記載のカプセル。
- 500μm未満の直径を有する、請求項1乃至9の何れかに記載のカプセル。
- 前記カプセルが前記半透性膜内に配置された内部コアを含み、当該内部コアがヒト細胞組成物と当該ヒト細胞組成物用のマトリクスとを備える、請求項1乃至10の何れかに記載のカプセル。
- 前記内部コアが相互接続した細孔を有する網状の発泡体からなる足場を備え、当該発泡体の細孔の密度が20%乃至90%であり、かつ、前記細胞が当該細孔内に分散する、請求項1乃至11の何れかに記載のカプセル。
- 前記発泡体からなる足場がヒドロゲル、熱可塑性プラスチック、又は熱可塑性エラストマーである、請求項1乃至12の何れかに記載のカプセル。
- 前記半透性膜は、前記コア内の細胞と前記カプセルの外部の細胞との間における細胞同士の接触を防止することが可能である、請求項2乃至13の何れかに記載のカプセル。
- 前記半透性膜が免疫隔離性である、請求項2乃至14の何れかに記載のカプセル。
- 前記半透性膜が細孔性である、請求項2乃至15の何れかに記載のカプセル。
- 前記膜が1000kDa以下の分画分子量を有する、請求項1乃至16の何れかに記載のカプセル。
- 前記カプセルがジャケットを備え、当該ジャケットの厚さが2乃至200ミクロンである、請求項1乃至17の何れかに記載のカプセル。
- 係留具を更に備える、請求項1乃至18の何れかに記載のカプセル。
- 縫合穴を更に備える、請求項1乃至19の何れかに記載のカプセル。
- 前記係留具は、前記カプセルの取り付け及び除去に使用することができる、請求項19又は20記載のカプセル。
- 前記細胞は、貪食が可能である、請求項1乃至21の何れかに記載のカプセル。
- 前記細胞が非腫瘍原性である、請求項1乃至22の何れかに記載のカプセル。
- 前記細胞が哺乳動物、又はヒトにおいて、非腫瘍原性である、請求項1乃至23の何れかに記載のカプセル。
- 前記細胞が異種不死化遺伝子、SV40T、vmyc、又はテロメラーゼの触媒サブユニットであるTERTの挿入により不死化されている、請求項1乃至24の何れかに記載のカプセル。
- 前記細胞が異種不死化遺伝子の挿入により不死化されていない、請求項1乃至24の何れかに記載のカプセル。
- 前記細胞は、酸素圧5%未満において生存が可能である、請求項1乃至26の何れかに記載のカプセル。
- 前記細胞が初代培養を起源とする、請求項1乃至27の何れかに記載のカプセル。
- 前記細胞は、少なくとも50回の倍加を起こすことが可能である、請求項1乃至28の何れかに記載のカプセル。
- 前記細胞が低レベルのヒト宿主免疫反応を引き起こし、ヒト抗体及び/又は補体依存性細胞毒性が非ヒト動物に比べ、ヒトにおいて低くなる、請求項1乃至29の何れかに記載のカプセル。
- 前記細胞がヒト幹細胞株の細胞である、請求項30記載のカプセル。
- 前記細胞がヒト星状細胞株の細胞である、請求項30記載のカプセル。
- 前記細胞がヒト中脳細胞株の細胞である、請求項30記載のカプセル。
- 前記細胞がヒト上皮細胞株の細胞である、請求項30記載のカプセル。
- 前記細胞が網膜色素上皮(RPE)細胞株の細胞又は初代RPE細胞である、請求項30記載のカプセル。
- 前記細胞がARPE-19由来細胞株の細胞である、請求項30記載のカプセル。
- 前記細胞がヒト単クローン細胞株の細胞である、請求項30乃至36の何れかに記載のカプセル。
- 前記発現コンストラクトがプロモーターを含む、請求項1乃至37の何れかに記載のカプセル。
- 前記プロモーターがCAGプロモーター、CMVプロモーター、ヒトUbiCプロモーター、JeTプロモーター、RSVプロモーター、EF-1αプロモーター、SV40プロモーター、及びMt1プロモーターからなる群から選択される恒常的活性プロモーターである、請求項38記載のカプセル。
- 前記プロモーターがTet-Onプロモーター、Tet-Offプロモーター、Mo-MLV-LTRプロモーター、Mx1プロモーター、プロゲステロンプロモーター、RU486誘導性プロモーター、及びラパマイシン誘導性プロモーターからなる群から選択される誘導性プロモーターである、請求項38記載のカプセル。
- 前記発現コンストラクトが、コザックコンセンサス配列と、ウッドチャック肝炎ウイルス転写後調節エレメントと、WPREと、SP163エンハンサーと、CMVエンハンサーと、tau、TH、又はAPP遺伝子からの非翻訳5'又は3'領域と、ニワトリβグロビンインスレーターとからなる群から選択される発現促進配列を含む、請求項1乃至40の何れかに記載のカプセル。
- 前記発現コンストラクトが、コザックコンセンサス配列、WPRE、及びニワトリβグロビンインスレーターからなる群から選択される発現促進配列を含む、請求項1乃至41の何れかに記載のカプセル。
- 前記構造遺伝子が治療的に関連性のある遺伝子をコードする、請求項1乃至42の何れかに記載のカプセル。
- 前記構造遺伝子が塩基性線維芽細胞成長因子(bFGF)、酸性線維芽細胞成長因子、上皮細胞増殖因子、形質転換成長因子α、形質転換成長因子β、神経成長因子、インスリン様成長因子、血小板由来成長因子、腫瘍壊死因子α、線維芽細胞成長因子受容体、及び上皮細胞増殖因子受容体からなる群から選択される、請求項1乃至43の何れかに記載のカプセル。
- 前記構造遺伝子がグリア細胞由来神経栄養因子(GDNF)、ニュールツリン、アルテミン、パーセフィン、脳由来神経栄養因子、毛様体神経栄養因子、ホルボール12-ミリステート13-アセテートトリオホチン、アクチビン、及びサイロトロピン放出ホルモンからなる群から選択される、請求項1乃至44の何れかに記載のカプセル。
- 前記構造遺伝子がスタウロスポリン及びCGP-41251からなる群から選択される、請求項1乃至45の何れかに記載のカプセル。
- 前記構造遺伝子が骨形成タンパク質、マクロファージ炎症性タンパク質、ヘパリン硫酸塩、アンフィレギュリン、レチノイン酸、ホルモン、インターロイキン、及びヘパリン様の分子からなる群から選択される、請求項1乃至46の何れかに記載のカプセル。
- 前記構造遺伝子が抗体、ヒト抗体、ヒト化抗体、キメラ抗体、抗体の抗原結合性断片、Fv、scFv、Fab、Fab'、F(ab)2、2量体IgA分子、5価IgM、アフィボディ及びダイアボディからなる群から選択される、請求項1乃至47の何れかに記載のカプセル。
- 前記構造遺伝子がガラニン、神経ペプチドY、オレキシンA、オレキシンB、エンケファリン、ソマトスタチン14、ソマトスタチン28、血管活性腸管ペプチド、腸管ペプチドPHV-42、腸管ペプチドPHV-27、サブスタンスP、ニューロテンシン、コレシストキニン58、コレシストキニン39、コレシストキニン33、コレシストキニン25、コレシストキニン18、コレシストキニン12、コレシストキニン8、コレシストキニン7、コレシストキニン5、サブスタンスP、神経ペプチドK、神経ペプチドγ、ニューロキニンA、TRH、NGFからなる群から選択される、請求項1乃至48の何れかに記載のカプセル。
- 前記構造遺伝子がガラニン、コレシストキニン、ニューロテンシン、サブスタンスP、神経ペプチドK、神経ペプチドγ、ニューロキニンA、血管活性腸管ペプチド、オレキシンBからなる群から選択される、請求項1乃至49の何れかに記載のカプセル。
- 前記構造遺伝子がガラニン、神経ペプチドY、オレキシンA、オレキシンBからなる群から選択される、請求項49記載のカプセル。
- 前記構造遺伝子がガラニンである、請求項49乃至51の何れかに記載のカプセル。
- 前記構造遺伝子が成長因子又は栄養因子をコードする、請求項1乃至52の何れかに記載のカプセル。
- 前記因子が神経栄養因子である、請求項1乃至53の何れかに記載のカプセル。
- 前記構造遺伝子が抗体又は抗体の結合性断片をコードする、請求項1乃至54の何れかに記載のカプセル。
- 前記構造遺伝子がNGFである、請求項1乃至55の何れかに記載のカプセル。
- 前記NGFのコード配列が異種シグナルペプチドを有する成熟NGFをコードする、請求項1乃至56の何れかに記載のカプセル。
- 前記NGFのコード配列が異種プロペプチドを有する成熟NGFをコードする、請求項1乃至57の何れかに記載のカプセル。
- 前記構造遺伝子は、AADC(芳香族アミノ酸デカルボキシラーゼ)、TH(チロシン水酸化酵素)、GCH1(GTPシクロヒドロラーゼ1)、ドーパミン合成のための酵素、GAD(グルタミン酸脱炭酸酵素)、GABA合成のための酵素、又は小分子の生合成に関与するポリペプチドをコードする、請求項1乃至58の何れかに記載のカプセル。
- 前記構造遺伝子が、アデノシン合成及び分泌を促進するために、アデノシンキナーゼ又は内因性タンパク質を下方制御するsiRNAをコードする、請求項1乃至59の何れかに記載のカプセル。
- 前記カプセルが、 少なくとも20ng/カプセル/24時間で成長因子を分泌することができる、請求項1乃至60の何れかに記載のカプセル。
- 前記カプセルが、 少なくとも20ng/カプセル/24時間で神経ペプチドを分泌することができる、請求項1乃至61の何れかに記載のカプセル。
- 前記構造遺伝子のコピー数が2乃至25である、請求項1乃至62の何れかに記載のカプセル。
- 前記 2つの逆方向反復が、配列番号:5及び配列番号:6により特定されるヌクレオチド配列を含む、請求項1乃至63の何れかに記載のカプセル。
- 前記2つの逆方向反復が、配列番号7のアミノ酸配列又は以下の群から選択される突然変異又は突然変異群のうち少なくとも1つを含む1乃至20個のアミノ酸により配列番号7とは異なるアミノ酸配列を有するSleeping Beautyトランスポザーゼの基質である、請求項1乃至64の何れかに記載のカプセル:
- K14R;
- K13D;
- K13A;
- K30R;
- K33A;
- T83A;
- I100L;
- R115H;
- R143L;
- R147E;
- A205K/H207V/K208R/D210E;
- H207V/K208R/D210E;
- R214D/K215A/E216V/N217Q;
- M243H;
- M243Q;
- E267D;
- T314N; 及び
- G317E。 - 前記2つの逆方向反復が、配列番号8又は配列番号9のアミノ酸配列を有するSleeping Beautyトランスポザーゼの基質である、請求項1乃至65の何れかに記載のカプセル。
- 治療に使用するための、請求項1乃至66の何れかに記載のカプセル。
- 前記カプセルが非ヒトにおける埋込に使用される、請求項1乃至67の何れかに記載のカプセル。
- 前記カプセルがヒトにおける埋込に使用される、請求項67記載のカプセル。
- 前記埋込が脳に対するものである、請求項67乃至69の何れかに記載のカプセル。
- 分泌生物活性化合物を被験者へ送達するためのカプセルを生産する方法であって、当該カプセルは、
a. 生体適合性を有する外膜及び内部コアを備え、
b. 当該内部コアは、ヒト単クローン接触抑制性細胞を含み、
当該細胞は、構造遺伝子を有する異種発現コンストラクトを含み、当該構造遺伝子は、
i. 分泌生物活性ポリペプチドをコードするか、或いは、
ii. 生物活性を有する分泌化合物の細胞内での生成に寄与するポリペプチド又はsiRNAをコードし、
当該遺伝子は、Sleeping Beautyトランスポザーゼの基質である2つの逆方向反復間に位置する、カプセルであり、かつ、
当該方法は、当該異種発現コンストラクトをSleeping Beautyトランスポザーゼを使用して当該細胞のゲノムに挿入する工程を含む、方法。
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