JP2021503961A - マルチキメラ細胞、および、移植のための治療および免疫不全および遺伝性障害の処置 - Google Patents
マルチキメラ細胞、および、移植のための治療および免疫不全および遺伝性障害の処置 Download PDFInfo
- Publication number
- JP2021503961A JP2021503961A JP2020546311A JP2020546311A JP2021503961A JP 2021503961 A JP2021503961 A JP 2021503961A JP 2020546311 A JP2020546311 A JP 2020546311A JP 2020546311 A JP2020546311 A JP 2020546311A JP 2021503961 A JP2021503961 A JP 2021503961A
- Authority
- JP
- Japan
- Prior art keywords
- cells
- stem cells
- chimeric
- hematopoietic stem
- fusion
- 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
- 208000028782 Hereditary disease Diseases 0.000 title claims abstract description 21
- 238000011282 treatment Methods 0.000 title claims abstract description 21
- 238000002054 transplantation Methods 0.000 title claims abstract description 18
- 208000029462 Immunodeficiency disease Diseases 0.000 title claims abstract description 17
- 230000007813 immunodeficiency Effects 0.000 title claims abstract description 17
- 210000004027 cell Anatomy 0.000 claims abstract description 207
- 210000003958 hematopoietic stem cell Anatomy 0.000 claims abstract description 77
- 230000004927 fusion Effects 0.000 claims abstract description 55
- 210000002901 mesenchymal stem cell Anatomy 0.000 claims abstract description 41
- 210000001057 smooth muscle myoblast Anatomy 0.000 claims abstract description 23
- 230000001114 myogenic effect Effects 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims description 32
- 210000003098 myoblast Anatomy 0.000 claims description 21
- 201000006938 muscular dystrophy Diseases 0.000 claims description 20
- 210000003668 pericyte Anatomy 0.000 claims description 16
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 210000001185 bone marrow Anatomy 0.000 claims description 14
- 210000000056 organ Anatomy 0.000 claims description 12
- 230000000735 allogeneic effect Effects 0.000 claims description 10
- 210000004700 fetal blood Anatomy 0.000 claims description 7
- 230000034217 membrane fusion Effects 0.000 claims description 7
- 101710169336 5'-deoxyadenosine deaminase Proteins 0.000 claims description 6
- 102000055025 Adenosine deaminases Human genes 0.000 claims description 6
- 208000007502 anemia Diseases 0.000 claims description 6
- 238000011161 development Methods 0.000 claims description 6
- 208000007056 sickle cell anemia Diseases 0.000 claims description 6
- 208000018240 Bone Marrow Failure disease Diseases 0.000 claims description 4
- 206010065553 Bone marrow failure Diseases 0.000 claims description 4
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 4
- 230000007812 deficiency Effects 0.000 claims description 4
- 208000032839 leukemia Diseases 0.000 claims description 4
- 210000005259 peripheral blood Anatomy 0.000 claims description 4
- 239000011886 peripheral blood Substances 0.000 claims description 4
- 206010003594 Ataxia telangiectasia Diseases 0.000 claims description 3
- 206010010099 Combined immunodeficiency Diseases 0.000 claims description 3
- 206010025323 Lymphomas Diseases 0.000 claims description 3
- 208000034578 Multiple myelomas Diseases 0.000 claims description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 3
- 238000011134 hematopoietic stem cell transplantation Methods 0.000 claims description 3
- 238000010255 intramuscular injection Methods 0.000 claims description 3
- 239000007927 intramuscular injection Substances 0.000 claims description 3
- 238000010253 intravenous injection Methods 0.000 claims description 3
- 208000015872 Gaucher disease Diseases 0.000 claims description 2
- 210000003743 erythrocyte Anatomy 0.000 claims description 2
- 208000011580 syndromic disease Diseases 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 abstract description 4
- 239000000203 mixture Substances 0.000 description 26
- 210000000130 stem cell Anatomy 0.000 description 23
- 208000024908 graft versus host disease Diseases 0.000 description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 19
- 208000009329 Graft vs Host Disease Diseases 0.000 description 18
- 239000002202 Polyethylene glycol Substances 0.000 description 12
- 229920001223 polyethylene glycol Polymers 0.000 description 12
- 201000010099 disease Diseases 0.000 description 11
- 239000000463 material Substances 0.000 description 10
- 230000007910 cell fusion Effects 0.000 description 9
- 208000035475 disorder Diseases 0.000 description 8
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 6
- 229930195725 Mannitol Natural products 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 239000000594 mannitol Substances 0.000 description 6
- 235000010355 mannitol Nutrition 0.000 description 6
- 241000894007 species Species 0.000 description 6
- -1 CD31 − Proteins 0.000 description 5
- 206010013801 Duchenne Muscular Dystrophy Diseases 0.000 description 5
- 206010061598 Immunodeficiency Diseases 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 230000001332 colony forming effect Effects 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 210000002540 macrophage Anatomy 0.000 description 5
- 239000005022 packaging material Substances 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 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
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 101000800116 Homo sapiens Thy-1 membrane glycoprotein Proteins 0.000 description 4
- 102100033523 Thy-1 membrane glycoprotein Human genes 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 239000000975 dye Substances 0.000 description 4
- 238000000684 flow cytometry Methods 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 239000000600 sorbitol Substances 0.000 description 4
- 235000010356 sorbitol Nutrition 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 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
- 241000711408 Murine respirovirus Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 208000017763 cutaneous neuroendocrine carcinoma Diseases 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 210000003714 granulocyte Anatomy 0.000 description 3
- 230000002519 immonomodulatory effect Effects 0.000 description 3
- 230000001506 immunosuppresive effect Effects 0.000 description 3
- 210000003205 muscle Anatomy 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- 208000010543 22q11.2 deletion syndrome Diseases 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 208000000398 DiGeorge Syndrome Diseases 0.000 description 2
- 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 2
- 238000002965 ELISA Methods 0.000 description 2
- 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 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 206010062016 Immunosuppression Diseases 0.000 description 2
- 208000026350 Inborn Genetic disease Diseases 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
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 2
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 2
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 2
- 102000007562 Serum Albumin Human genes 0.000 description 2
- 108010071390 Serum Albumin Proteins 0.000 description 2
- 101150052863 THY1 gene Proteins 0.000 description 2
- 206010052779 Transplant rejections Diseases 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 210000004271 bone marrow stromal cell Anatomy 0.000 description 2
- 239000004067 bulking agent Substances 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 238000002659 cell therapy Methods 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000004624 confocal microscopy Methods 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 238000005538 encapsulation Methods 0.000 description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 238000003205 genotyping method Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 235000001727 glucose Nutrition 0.000 description 2
- 230000003394 haemopoietic effect Effects 0.000 description 2
- 238000009396 hybridization Methods 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 230000006058 immune tolerance Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 210000003593 megakaryocyte Anatomy 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 238000002406 microsurgery Methods 0.000 description 2
- 210000005087 mononuclear cell Anatomy 0.000 description 2
- 210000001087 myotubule Anatomy 0.000 description 2
- 210000005055 nestin Anatomy 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 235000010199 sorbic acid Nutrition 0.000 description 2
- 239000004334 sorbic acid Substances 0.000 description 2
- 229940075582 sorbic acid Drugs 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- LVZIWKFQFKNSMO-UHFFFAOYSA-N 1-chlorobutan-1-ol Chemical class CCCC(O)Cl LVZIWKFQFKNSMO-UHFFFAOYSA-N 0.000 description 1
- 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
- 102100022464 5'-nucleotidase Human genes 0.000 description 1
- 102100031585 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Human genes 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 102000005369 Aldehyde Dehydrogenase Human genes 0.000 description 1
- 108020002663 Aldehyde Dehydrogenase Proteins 0.000 description 1
- 108700028369 Alleles Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 1
- 201000006935 Becker muscular dystrophy Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 102100032912 CD44 antigen Human genes 0.000 description 1
- 102100024153 Cadherin-15 Human genes 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102100036912 Desmin Human genes 0.000 description 1
- 108010044052 Desmin Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000605732 Erythrophyllum Species 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 102100027286 Fanconi anemia group C protein Human genes 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000678236 Homo sapiens 5'-nucleotidase Proteins 0.000 description 1
- 101000777636 Homo sapiens ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Proteins 0.000 description 1
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 1
- 101000980840 Homo sapiens CD166 antigen Proteins 0.000 description 1
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 description 1
- 101000881679 Homo sapiens Endoglin Proteins 0.000 description 1
- 101001046677 Homo sapiens Integrin alpha-V Proteins 0.000 description 1
- 101000935043 Homo sapiens Integrin beta-1 Proteins 0.000 description 1
- 101000581981 Homo sapiens Neural cell adhesion molecule 1 Proteins 0.000 description 1
- 101000716102 Homo sapiens T-cell surface glycoprotein CD4 Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102100025323 Integrin alpha-1 Human genes 0.000 description 1
- 102100022337 Integrin alpha-V Human genes 0.000 description 1
- 108010041341 Integrin alpha1 Proteins 0.000 description 1
- 102100025304 Integrin beta-1 Human genes 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 102100022745 Laminin subunit alpha-2 Human genes 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 108010018562 M-cadherin Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000024556 Mendelian disease Diseases 0.000 description 1
- 108091092878 Microsatellite Proteins 0.000 description 1
- 201000001087 Miyoshi muscular dystrophy Diseases 0.000 description 1
- 208000009376 Miyoshi myopathy Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 102100027347 Neural cell adhesion molecule 1 Human genes 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 102100024616 Platelet endothelial cell adhesion molecule Human genes 0.000 description 1
- 108010051742 Platelet-Derived Growth Factor beta Receptor Proteins 0.000 description 1
- 101710164680 Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- 229920012266 Poly(ether sulfone) PES Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 241000700159 Rattus Species 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
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- 108010000134 Vascular Cell Adhesion Molecule-1 Proteins 0.000 description 1
- 102100023543 Vascular cell adhesion protein 1 Human genes 0.000 description 1
- 102000013127 Vimentin Human genes 0.000 description 1
- 108010065472 Vimentin Proteins 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 201000006793 Walker-Warburg syndrome Diseases 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229910001508 alkali metal halide Inorganic materials 0.000 description 1
- 150000008045 alkali metal halides Chemical class 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 238000011316 allogeneic transplantation Methods 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 238000013475 authorization Methods 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 210000002960 bfu-e Anatomy 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 150000001642 boronic acid derivatives Chemical class 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 239000002771 cell marker Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 210000002791 cfu-m Anatomy 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 229960003260 chlorhexidine Drugs 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 210000001612 chondrocyte Anatomy 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 230000003021 clonogenic effect Effects 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 201000006815 congenital muscular dystrophy Diseases 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002316 cosmetic surgery Methods 0.000 description 1
- 210000004544 dc2 Anatomy 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 210000005045 desmin Anatomy 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 201000009338 distal myopathy Diseases 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000000267 erythroid cell Anatomy 0.000 description 1
- 230000003090 exacerbative effect Effects 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 210000003195 fascia Anatomy 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000000799 fusogenic effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 238000011773 genetically engineered mouse model Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 210000000777 hematopoietic system Anatomy 0.000 description 1
- 230000001744 histochemical effect Effects 0.000 description 1
- 229960002163 hydrogen peroxide Drugs 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000003365 immunocytochemistry Methods 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 230000006057 immunotolerant effect Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 210000003716 mesoderm Anatomy 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 210000004088 microvessel Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 238000001964 muscle biopsy Methods 0.000 description 1
- 230000037257 muscle growth Effects 0.000 description 1
- 230000009756 muscle regeneration Effects 0.000 description 1
- 210000000107 myocyte Anatomy 0.000 description 1
- 230000003274 myotonic effect Effects 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000003924 normoblast Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 238000007500 overflow downdraw method Methods 0.000 description 1
- 238000002559 palpation Methods 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000000123 paper Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 208000026526 progressive weakness Diseases 0.000 description 1
- 230000000135 prohibitive effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000001902 propagating effect Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000002278 reconstructive surgery Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000000405 serological effect Effects 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000012289 standard assay Methods 0.000 description 1
- 238000011476 stem cell transplantation Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 230000003614 tolerogenic effect Effects 0.000 description 1
- 239000012443 tonicity enhancing agent Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 238000011277 treatment modality Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 210000005048 vimentin Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 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
- C12N5/10—Cells modified by introduction of foreign genetic material
- C12N5/12—Fused cells, e.g. hybridomas
- C12N5/16—Animal cells
-
- 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
- A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
-
- 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
- A61K35/34—Muscles; Smooth muscle cells; Heart; Cardiac stem cells; Myoblasts; Myocytes; Cardiomyocytes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/461—Cellular immunotherapy characterised by the cell type used
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/462—Cellular immunotherapy characterized by the effect or the function of the cells
- A61K39/4621—Cellular immunotherapy characterized by the effect or the function of the cells immunosuppressive or immunotolerising
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/46433—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/46434—Antigens related to induction of tolerance to non-self
-
- 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
- C12N5/0603—Embryonic cells ; Embryoid bodies
- C12N5/0605—Cells from extra-embryonic tissues, e.g. placenta, amnion, yolk sac, Wharton's jelly
-
- 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
- C12N5/0634—Cells from the blood or the immune system
-
- 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
- A61K2035/122—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells for inducing tolerance or supression of immune responses
-
- 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
- A61K2035/124—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells the cells being hematopoietic, bone marrow derived or blood cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterized by the route of administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Chemical & Material Sciences (AREA)
- Cell Biology (AREA)
- Zoology (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Developmental Biology & Embryology (AREA)
- Wood Science & Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Microbiology (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- General Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Hematology (AREA)
- Gynecology & Obstetrics (AREA)
- Virology (AREA)
- Reproductive Health (AREA)
- Mycology (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Pregnancy & Childbirth (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
Description
本出願は、2017年11月28日出願の米国仮特許出願第62/591,397号(この内容はその全体が参照されることによって本明細書に組み込まれる)に対する優先権の利益を主張するものである。
幹細胞移植は、多くのヒト障害の処置のための有望な新ストラテジーである。造血幹細胞(HSC)移植は、幹細胞をベースとした治療(therapies)の治療可能性(curative potential)についての最もためになる例である。自己HSCは多くの血液病にとって処置選択肢にはなり得ない一方で、同種異系間の幹細胞移植片の入手可能性は、血縁関係にある(related)適合ドナーの不足(lack)に起因し限定されている。加えて、血縁関係にない(unrelated)適合HSC移植は、前処置レジメン(conditioning regimens)および移植片対宿主病(GvHD)の毒性効果に起因するしばしば酷く高い(prohibitive)死亡率および罹患率によって阻まれる。GvHDのリスクなく組織適合性という障壁を越えて、生着率または有効性および移植実施能を改善することは、多くの、しばしば不治の疾患にとって、選り抜きの新しい処置モダリティ(modality)としてのHSC移植の適用を大いに増大させるであろう。
本発明は、3体以上の異なるドナーからの、3種以上の造血幹細胞、間葉系幹細胞、筋原細胞(myoblasts)、周皮細胞、衛星細胞、またはそれらの組み合わせの融合体(fusion)から構成される(composed of)マルチキメラ細胞(multi-chimeric cell)である。ある態様において、造血幹細胞は、骨髄、臍帯血、末梢血、またはそれらの組み合わせから単離されたものである。他の態様において、ドナー同士(donors)は、血縁関係にあるか、血縁関係にないか、またはそれらの組み合わせである。いくつかの態様において、融合体は、造血幹細胞と、独立して、造血幹細胞および間葉系幹細胞から選択される2種以上の細胞との組み合わせである。他の態様において、融合体は、造血幹細胞と、独立して、造血幹細胞、間葉系幹細胞、および周皮細胞から選択される2種以上の細胞との組み合わせである。他の態様において、融合体は、筋原細胞と、独立して、間葉系幹細胞、筋原細胞、および衛星細胞から選択される2種の細胞との組み合わせである。具体的な態様において、融合体は、造血幹細胞、間葉系幹細胞、および周皮細胞;3種の造血幹細胞;筋原細胞、間葉系幹、および衛星細胞;または、3種の筋芽細胞(myoblast cells)の組み合わせである。膜融合剤(fusogenic agent)、および3体以上の異なるドナーからの、造血幹細胞、間葉系幹細胞、筋原細胞、周皮細胞、衛星細胞の群から選択される3種以上のドナー細胞を包含するキットもまた提供される。
移植治療のための、かつ免疫不全および遺伝性障害をもつ患者を処置するためのマルチキメラ細胞が今や開発された。本発明のマルチキメラ細胞は、少なくとも3種(トリメラ(trimera))またはそれ以上(四重キメラおよび多重生成キメラ(multi-generation chimera)等々)の血縁関係にあるかおよび/または血縁関係にないドナーに由来するヒト造血幹細胞(自己および/または同種異系)の融合によって創出された(図1)。具体的に言うと、複数生成(multiple-generations)のキメラ細胞は、造血起源(hematopoietic origin)の細胞:造血幹細胞(HSCs)または臍帯血(UCB)細胞または骨髄(BM)細胞、あるいはHSCおよび/またはUCBおよび/またはBMの組み合わせのPEG媒介ex-vivo融合を介して創出された。その結果得られたマルチキメラ細胞は、それらの表面上に、複数の細胞ドナー夫々に特異的なHLA抗原を発現していた。マルチキメラ細胞によって確立された微小環境は、免疫抑制および前処置レジメンの副作用を軽減し、かつGvHDなくHSC生着を増強する。本アプローチは、様々な免疫学的障害および遺伝性障害の処置を可能にさせるであろう。
マルチキメラ細胞(MCC)を、3体以上の血縁関係にあるかおよび/または血縁関係にないドナーからの、ならびに1種以上の造血幹細胞の供給源、すなわち骨髄(「BM」)、末梢血(「PB」)、および/または臍帯血(「UCB」)、例として、市販の供給源からの、ヒト造血細胞のex vivo細胞融合によって生成する。
血縁関係にない3体のドナーからのヒトUCB細胞の30の個々の融合を図1に示されるとおり実施した。共焦点顕微鏡法およびフローサイトメトリーによって、ex vivo融合が生じたことが、三重(PKH26/PKH67/eFluor 670)蛍光標識されたMCCsの存在によって確認された。MCCsの表現型の追加の特徴もまた評価した。とりわけ、ex vivo融合手順は、対照(すなわちeFluor670増殖色素標識されたUCB細胞)と比較しても、MCCsによるCD4、CD90、CD45、およびCD19の発現を変化させなかったことが見出された。さらにまた、MCCsの90〜95%は、トリパンブルー染色によって決定されるとおり、生存能力があった。増殖性の特性を、多中心性の(multicentric)、多能性の(multipotential)顆粒球・赤芽球・マクロファージ・巨核球コロニー形成単位(granulocyte, erythroid, macrophage, megakaryocyte colony forming units)(CFU-GEMM)、顆粒球コロニー形成単位(CFU-G)、顆粒球-マクロファージコロニー形成単位(CFU-GM)、マクロファージコロニー形成単位(CFU-M)、および赤芽球バースト形成単位(BFU-E)アッセイを包含するin vivoでのコロニー形成単位アッセイによって決定した。血清学的HLAタイピングを使用するMCCsの遺伝子型分析によって、MCCの遺伝物質(genetic material)中に、血縁関係にない3体のドナー各々に特異的なアレルが存在していたことが確認された(表4)。
Claims (20)
- 3体以上の異なるドナーからの3種以上の造血幹細胞、間葉系幹細胞、筋原細胞、周皮細胞、衛星細胞、またはそれらの組み合わせのex vivo融合体を含む、マルチキメラ細胞。
- 造血幹細胞と、独立して、造血幹細胞および間葉系幹細胞から選択される2種以上の細胞とのex vivo融合体からなる、請求項1に記載のマルチキメラ細胞。
- 造血幹細胞が、骨髄、臍帯血、末梢血、またはそれらの組み合わせから単離されたものである、請求項1に記載のマルチキメラ細胞。
- ドナー同士が、血縁関係にあるか、血縁関係にないか、またはそれらの組み合わせである、請求項1に記載のマルチキメラ細胞。
- 造血幹細胞と、独立して、造血幹細胞、間葉系幹細胞、および周皮細胞から選択される2種以上の細胞とのex vivo融合体からなる、請求項1に記載のマルチキメラ細胞。
- 造血幹細胞、間葉系幹細胞、および周皮細胞のex vivo融合体からなる、請求項5に記載のマルチキメラ細胞。
- 3種の造血幹細胞のex vivo融合体からなる、請求項5に記載のマルチキメラ細胞。
- 筋原細胞と、独立して、間葉系幹細胞、筋原細胞、および衛星細胞から選択される2種の細胞とのex vivo融合体からなる、請求項1に記載のマルチキメラ細胞。
- 筋原細胞、間葉系幹、および衛星細胞のex vivo融合体からなる、請求項8に記載のマルチキメラ細胞。
- 3種の筋芽細胞のex vivo融合体からなる、請求項8に記載のマルチキメラ細胞。
- 免疫不全または遺伝性障害を処置する方法であって、請求項1に記載のマルチキメラ細胞の有効量を、処置を必要とする対象へ投与すること、それによって対象の免疫不全または遺伝性障害を処置することを含む、前記方法。
- マルチキメラ細胞が、骨内の、静脈内の、または筋肉内の注射によって投与される、請求項11に記載の方法。
- 免疫不全または遺伝性障害が、骨髄不全、アデノシンデアミナーゼ(ADA)欠損症、重症複合免疫不全症(SCID)、ディジョージ症候群、毛細血管拡張性運動失調症、筋ジストロフィー、I型糖尿病、ゴーシェ病、白血病、再生不良性貧血、鎌状赤血球貧血、リンパ腫、および多発性骨髄腫から選択される、請求項11に記載の方法。
- 遺伝性障害が、筋ジストロフィーである、請求項11に記載の方法。
- マルチキメラ細胞が、筋原細胞と、独立して、間葉系幹細胞、筋原細胞、および衛星細胞から選択される2種以上の細胞とのex vivo融合体を含む、請求項14に記載の方法。
- 免疫不全または遺伝性障害が、鎌状赤血球貧血である、請求項11に記載の方法。
- マルチキメラ細胞が、造血幹細胞と、独立して、造血幹細胞および間葉系幹細胞から選択される2種以上の細胞とのex vivo融合体を含む、請求項16に記載の方法。
- 同種異系間の造血幹細胞移植もしくは臓器移植を受けている対象においてGvHDの発症を予防するかまたはGvHDの重症度を低減する方法であって、請求項1に記載のマルチキメラ細胞の有効量を対象へ投与すること、それによって対象におけるGvHDの発症を予防するかまたはGvHDの重症度を低減することを含む、前記方法。
- マルチキメラ細胞が、造血幹細胞と、独立して、造血幹細胞および間葉系幹細胞から選択される2種以上の細胞とのex vivo融合体を含む、請求項18に記載の方法。
- (a)膜融合剤、および
(b)3体以上の異なるドナーからの造血幹細胞、間葉系幹細胞、筋原細胞、周皮細胞、衛星細胞の群から選択される3種以上のドナー細胞
を含む、キット。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762591397P | 2017-11-28 | 2017-11-28 | |
US62/591,397 | 2017-11-28 | ||
PCT/US2018/062736 WO2019108584A1 (en) | 2017-11-28 | 2018-11-28 | Multi-chimeric cell and therapy for transplantation and treatment of immune deficiencies and genetic disorders |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2021503961A true JP2021503961A (ja) | 2021-02-15 |
JP2021503961A5 JP2021503961A5 (ja) | 2021-12-23 |
Family
ID=64949384
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020546311A Pending JP2021503961A (ja) | 2017-11-28 | 2018-11-28 | マルチキメラ細胞、および、移植のための治療および免疫不全および遺伝性障害の処置 |
Country Status (7)
Country | Link |
---|---|
US (1) | US20200263141A1 (ja) |
EP (1) | EP3717635A1 (ja) |
JP (1) | JP2021503961A (ja) |
CN (1) | CN111406106A (ja) |
AU (1) | AU2018375315A1 (ja) |
CA (1) | CA3116328A1 (ja) |
WO (1) | WO2019108584A1 (ja) |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004510821A (ja) * | 2000-10-11 | 2004-04-08 | ゲーエスエフ・フォルシュングスツェントゥルム・フューア・ウムヴェルト・ウント・ゲズントハイト・ゲーエムベーハー | 同種移植片に対する免疫寛容の誘導および/または白血病処置のための、幹細胞およびcd6枯渇幹細胞の使用 |
JP2004147531A (ja) * | 2002-10-29 | 2004-05-27 | Asahi Kasei Corp | 細胞処理方法 |
US20070253931A1 (en) * | 2006-01-12 | 2007-11-01 | Osiris Therapeutics, Inc. | Use of mesenchymal stem cells for treating genetic diseases and disorders |
JP2011514901A (ja) * | 2008-03-05 | 2011-05-12 | オシリス セラピューティクス,インコーポレイテッド | 遺伝子疾患および障害を治療するための間葉系幹細胞の使用 |
JP2011519900A (ja) * | 2008-05-07 | 2011-07-14 | ボーン セラピューティクス エス.アー. | 免疫不全又は免疫抑制と関連する病状及び骨疾患の治療におけるヒト骨形成性細胞 |
WO2016201182A1 (en) * | 2015-06-11 | 2016-12-15 | The Board Of Trustees Of The University Of Illinios | Muscular dystrophy chimeric cells and method for treating muscular dystrophies |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5538722A (en) | 1989-06-13 | 1996-07-23 | Stanford University | Isolation, growth, differentiation and genetic engineering of human muscle cells |
AU2003228768B2 (en) * | 2002-05-22 | 2009-02-05 | The Cleveland Clinic Foundation | Induction and maintenance of tolerance to composite tissue allografts |
WO2003102126A1 (en) * | 2002-05-31 | 2003-12-11 | Apollo Life Sciences Pty Ltd | A method of cell therapy using fused cell hybrids |
CA2475174A1 (en) | 2004-07-19 | 2006-01-19 | Institut Pasteur | Isolated muscle satellite cells, use thereof in muscle tissue repair and method for isolating said muscle satellite cells |
CA2703428A1 (en) * | 2010-05-11 | 2011-11-11 | Mcgill University Health Center | Pooled cord blood units |
WO2014087658A1 (en) * | 2012-12-07 | 2014-06-12 | Kuraray Co., Ltd. | Method of cell fusion and fusion cells |
US20150050300A1 (en) * | 2013-08-16 | 2015-02-19 | Peter K. Law | Disease prevention and alleviation by human myoblast transplantation |
US10071121B2 (en) * | 2014-11-14 | 2018-09-11 | San Diego State University (Sdsu) Foundation | Cardiac, mesenchymal and endothelial progenitor cell (CPC) chimeras and methods for making and using them |
-
2018
- 2018-11-28 EP EP18830033.9A patent/EP3717635A1/en active Pending
- 2018-11-28 CN CN201880076290.4A patent/CN111406106A/zh active Pending
- 2018-11-28 AU AU2018375315A patent/AU2018375315A1/en active Pending
- 2018-11-28 US US16/761,561 patent/US20200263141A1/en active Pending
- 2018-11-28 CA CA3116328A patent/CA3116328A1/en active Pending
- 2018-11-28 JP JP2020546311A patent/JP2021503961A/ja active Pending
- 2018-11-28 WO PCT/US2018/062736 patent/WO2019108584A1/en unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004510821A (ja) * | 2000-10-11 | 2004-04-08 | ゲーエスエフ・フォルシュングスツェントゥルム・フューア・ウムヴェルト・ウント・ゲズントハイト・ゲーエムベーハー | 同種移植片に対する免疫寛容の誘導および/または白血病処置のための、幹細胞およびcd6枯渇幹細胞の使用 |
JP2004147531A (ja) * | 2002-10-29 | 2004-05-27 | Asahi Kasei Corp | 細胞処理方法 |
US20070253931A1 (en) * | 2006-01-12 | 2007-11-01 | Osiris Therapeutics, Inc. | Use of mesenchymal stem cells for treating genetic diseases and disorders |
JP2011514901A (ja) * | 2008-03-05 | 2011-05-12 | オシリス セラピューティクス,インコーポレイテッド | 遺伝子疾患および障害を治療するための間葉系幹細胞の使用 |
JP2011519900A (ja) * | 2008-05-07 | 2011-07-14 | ボーン セラピューティクス エス.アー. | 免疫不全又は免疫抑制と関連する病状及び骨疾患の治療におけるヒト骨形成性細胞 |
WO2016201182A1 (en) * | 2015-06-11 | 2016-12-15 | The Board Of Trustees Of The University Of Illinios | Muscular dystrophy chimeric cells and method for treating muscular dystrophies |
Non-Patent Citations (3)
Title |
---|
J. NIHON UNIV. MED. ASS., vol. 74 (5), JPN6023014323, 2015, pages 227 - 229, ISSN: 0005136096 * |
JAPANESE JOURNAL OF TRANSFUSION MEDICINE, vol. 40, no. 5, JPN6023014324, 1994, pages 737 - 743, ISSN: 0005136097 * |
JOANNA CWYKIEL ET AL: "CHARACTERIZATION OF HUMAN MULTI-CHIMERIC CELLS A NEW TOLERANCE INDUCING CELLULAR THERAPY IN TRANSPLA", ABSTRACTS OF THE 18TH CONGRESS OF THE EUROPEAN SOCIETY FOR ORGAN TRANSPLANTATION, 24-27 SEPTEMBER 20, JPN7022004829, 19 August 2017 (2017-08-19), pages 302, ISSN: 0005136095 * |
Also Published As
Publication number | Publication date |
---|---|
CN111406106A (zh) | 2020-07-10 |
AU2018375315A1 (en) | 2020-06-04 |
EP3717635A1 (en) | 2020-10-07 |
CA3116328A1 (en) | 2019-12-06 |
WO2019108584A1 (en) | 2019-06-06 |
US20200263141A1 (en) | 2020-08-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Kim et al. | Clinical applications of mesenchymal stem cells | |
Sudres et al. | Bone marrow mesenchymal stem cells suppress lymphocyte proliferation in vitro but fail to prevent graft-versus-host disease in mice | |
JP2023153391A (ja) | 脳損傷及び疾患のmapc治療 | |
Caimi et al. | Emerging therapeutic approaches for multipotent mesenchymal stromal cells | |
JP5432527B2 (ja) | 脳損傷及び疾患のmapc治療 | |
Shaw et al. | Mesenchymal stromal cells: an antimicrobial and host-directed therapy for complex infectious diseases | |
BR112017014361B1 (pt) | Uso de uma população de células-tronco mesenquimais (MSCS) modificadas com fucosiltransferase VI (FTVI) que expressa o ligante de E-L Selectina de célula hematopoiética (HCELL) para tratar diabetes | |
AU2007247725A1 (en) | Immune privileged and modulatory progenitor cells | |
CN106470676A (zh) | 用于非细胞毒性干细胞移植的方法和组合物 | |
US20220025335A1 (en) | Muscular dystrophy chimeric cells and method for treating muscular dystrophies | |
WO2013168403A1 (ja) | トレハロース含有肺塞栓形成予防用哺乳動物細胞懸濁液 | |
US20160158292A1 (en) | Method and apparatus for recovery of umbilical cord tissue derived regenerative cells and uses thereof | |
JP2021503961A (ja) | マルチキメラ細胞、および、移植のための治療および免疫不全および遺伝性障害の処置 | |
Cetrulo et al. | Perinatal stem cells | |
US20160022743A1 (en) | Human very small embryonic-like (vsel) stem cells for treatment of ocular disease | |
US20240091269A1 (en) | Treatment of bipolar disorder using mesenchymal stem cells and modification of mesenchymal stem cells | |
Horwitz | Mesenchymal Stromal Cells and Hematopoietic Cell Transplantation | |
Bieback et al. | Non-hematopoietic stem and progenitor cells derived from human umbilical cord blood | |
Siemionow et al. | The Role of Stem Cells in Plastic Surgery | |
Peled et al. | 226Preferential expansion of cord blood early progenitors enabled by linear polyamine copper chelators | |
MX2008005940A (es) | Propiedades inmunomoduladoras de celulas progenitoras adultas multipotentes y sus usos |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20211112 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20211112 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20220922 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20221012 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230112 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230412 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230710 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20230825 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20231221 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20231221 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20240116 |
|
A912 | Re-examination (zenchi) completed and case transferred to appeal board |
Free format text: JAPANESE INTERMEDIATE CODE: A912 Effective date: 20240315 |