WO2021072595A1 - Utilisation médicale de cellules souches mésenchymateuses dans le traitement d'une déficience auditive - Google Patents
Utilisation médicale de cellules souches mésenchymateuses dans le traitement d'une déficience auditive Download PDFInfo
- Publication number
- WO2021072595A1 WO2021072595A1 PCT/CN2019/111034 CN2019111034W WO2021072595A1 WO 2021072595 A1 WO2021072595 A1 WO 2021072595A1 CN 2019111034 W CN2019111034 W CN 2019111034W WO 2021072595 A1 WO2021072595 A1 WO 2021072595A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- mesenchymal stem
- hearing impairment
- stem cells
- hearing
- cells
- Prior art date
Links
- 210000002901 mesenchymal stem cell Anatomy 0.000 title claims abstract description 89
- 208000016354 hearing loss disease Diseases 0.000 title claims abstract description 78
- 238000011282 treatment Methods 0.000 title abstract description 10
- 239000000203 mixture Substances 0.000 claims description 30
- 229960004316 cisplatin Drugs 0.000 claims description 22
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 20
- 238000002360 preparation method Methods 0.000 claims description 17
- 229940079593 drug Drugs 0.000 claims description 14
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 14
- 239000003937 drug carrier Substances 0.000 claims description 11
- 239000002246 antineoplastic agent Substances 0.000 claims description 10
- 231100000199 ototoxic Toxicity 0.000 claims description 10
- 230000002970 ototoxic effect Effects 0.000 claims description 10
- 208000016621 Hearing disease Diseases 0.000 claims description 8
- 229940044683 chemotherapy drug Drugs 0.000 claims description 8
- 229910052697 platinum Inorganic materials 0.000 claims description 7
- 239000007924 injection Substances 0.000 claims description 5
- 238000002347 injection Methods 0.000 claims description 5
- 239000006193 liquid solution Substances 0.000 claims description 3
- 239000006194 liquid suspension Substances 0.000 claims description 3
- 210000004027 cell Anatomy 0.000 description 34
- 210000002768 hair cell Anatomy 0.000 description 17
- 241001465754 Metazoa Species 0.000 description 16
- 210000001519 tissue Anatomy 0.000 description 15
- 239000002609 medium Substances 0.000 description 14
- 241000699670 Mus sp. Species 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- 210000002966 serum Anatomy 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 238000010171 animal model Methods 0.000 description 9
- 206010011878 Deafness Diseases 0.000 description 8
- 230000006378 damage Effects 0.000 description 8
- 231100000888 hearing loss Toxicity 0.000 description 8
- 230000010370 hearing loss Effects 0.000 description 8
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 7
- 210000003477 cochlea Anatomy 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 6
- 241000282412 Homo Species 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 210000000133 brain stem Anatomy 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000012074 hearing test Methods 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 210000003462 vein Anatomy 0.000 description 5
- 230000002354 daily effect Effects 0.000 description 4
- 210000003027 ear inner Anatomy 0.000 description 4
- 230000003203 everyday effect Effects 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 239000007928 intraperitoneal injection Substances 0.000 description 4
- 238000010172 mouse model Methods 0.000 description 4
- 235000015097 nutrients Nutrition 0.000 description 4
- 230000035945 sensitivity Effects 0.000 description 4
- 241000283086 Equidae Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 206010033109 Ototoxicity Diseases 0.000 description 3
- 230000032683 aging Effects 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 239000001569 carbon dioxide Substances 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 239000000306 component Substances 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 230000001744 histochemical effect Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 210000002894 multi-fate stem cell Anatomy 0.000 description 3
- 231100000262 ototoxicity Toxicity 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 239000003642 reactive oxygen metabolite Substances 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 210000000130 stem cell Anatomy 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 2
- 102100022464 5'-nucleotidase Human genes 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 102000029816 Collagenase Human genes 0.000 description 2
- 108060005980 Collagenase Proteins 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 102100037241 Endoglin Human genes 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 239000012981 Hank's balanced salt solution Substances 0.000 description 2
- 208000032041 Hearing impaired Diseases 0.000 description 2
- 101000678236 Homo sapiens 5'-nucleotidase Proteins 0.000 description 2
- 101000881679 Homo sapiens Endoglin Proteins 0.000 description 2
- 101000800116 Homo sapiens Thy-1 membrane glycoprotein Proteins 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- KPKZJLCSROULON-QKGLWVMZSA-N Phalloidin Chemical compound N1C(=O)[C@@H]([C@@H](O)C)NC(=O)[C@H](C)NC(=O)[C@H](C[C@@](C)(O)CO)NC(=O)[C@H](C2)NC(=O)[C@H](C)NC(=O)[C@@H]3C[C@H](O)CN3C(=O)[C@@H]1CSC1=C2C2=CC=CC=C2N1 KPKZJLCSROULON-QKGLWVMZSA-N 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 241000282887 Suidae Species 0.000 description 2
- 102100033523 Thy-1 membrane glycoprotein Human genes 0.000 description 2
- 206010070863 Toxicity to various agents Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 210000004102 animal cell Anatomy 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000012076 audiometry Methods 0.000 description 2
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- 239000006143 cell culture medium Substances 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 210000000860 cochlear nerve Anatomy 0.000 description 2
- 229960002424 collagenase Drugs 0.000 description 2
- 210000004748 cultured cell Anatomy 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 210000000883 ear external Anatomy 0.000 description 2
- 210000000959 ear middle Anatomy 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000009395 genetic defect Effects 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 230000036737 immune function Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 210000000067 inner hair cell Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000007898 magnetic cell sorting Methods 0.000 description 2
- 230000007721 medicinal effect Effects 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 230000008447 perception Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 230000008569 process 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
- 230000003997 social interaction Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 229960003433 thalidomide Drugs 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 229960001600 xylazine Drugs 0.000 description 2
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 2
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 1
- 108090000145 Bacillolysin Proteins 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 241000282832 Camelidae Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 241000819038 Chichester Species 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 102400000739 Corticotropin Human genes 0.000 description 1
- 101800000414 Corticotropin Proteins 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- ASXBYYWOLISCLQ-UHFFFAOYSA-N Dihydrostreptomycin Natural products O1C(CO)C(O)C(O)C(NC)C1OC1C(CO)(O)C(C)OC1OC1C(N=C(N)N)C(O)C(N=C(N)N)C(O)C1O ASXBYYWOLISCLQ-UHFFFAOYSA-N 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 208000027534 Emotional disease Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- -1 FGF and EGF) Chemical class 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 241000699694 Gerbillinae Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 241000282575 Gorilla Species 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 101000979342 Homo sapiens Nuclear factor NF-kappa-B p105 subunit Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 201000005505 Measles Diseases 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 206010062545 Middle ear effusion Diseases 0.000 description 1
- 206010052641 Mitochondrial DNA mutation Diseases 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- 208000005647 Mumps Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000282339 Mustela Species 0.000 description 1
- 102000003505 Myosin Human genes 0.000 description 1
- 108060008487 Myosin Proteins 0.000 description 1
- 102000026889 Myosin VIIa Human genes 0.000 description 1
- 108010009047 Myosin VIIa Proteins 0.000 description 1
- RTHCYVBBDHJXIQ-UHFFFAOYSA-N N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine Chemical compound C=1C=CC=CC=1C(CCNC)OC1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-UHFFFAOYSA-N 0.000 description 1
- 108010002998 NADPH Oxidases Proteins 0.000 description 1
- 102000004722 NADPH Oxidases Human genes 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102000035092 Neutral proteases Human genes 0.000 description 1
- 108091005507 Neutral proteases Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 101150006256 Otof gene Proteins 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 108010009711 Phalloidine Proteins 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- 108010040201 Polymyxins Proteins 0.000 description 1
- 206010037180 Psychiatric symptoms Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 206010039587 Scarlet Fever Diseases 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 208000009205 Tinnitus Diseases 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 206010045210 Tympanic Membrane Perforation Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- XSMVECZRZBFTIZ-UHFFFAOYSA-M [2-(aminomethyl)cyclobutyl]methanamine;2-oxidopropanoate;platinum(4+) Chemical compound [Pt+4].CC([O-])C([O-])=O.NCC1CCC1CN XSMVECZRZBFTIZ-UHFFFAOYSA-M 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 229960004538 alprazolam Drugs 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000002647 aminoglycoside antibiotic agent Substances 0.000 description 1
- BSJGASKRWFKGMV-UHFFFAOYSA-L ammonia dichloroplatinum(2+) Chemical compound N.N.Cl[Pt+2]Cl BSJGASKRWFKGMV-UHFFFAOYSA-L 0.000 description 1
- 210000001691 amnion Anatomy 0.000 description 1
- 210000004381 amniotic fluid Anatomy 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 238000012865 aseptic processing Methods 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 238000011130 autologous cell therapy Methods 0.000 description 1
- KLNFSAOEKUDMFA-UHFFFAOYSA-N azanide;2-hydroxyacetic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OCC(O)=O KLNFSAOEKUDMFA-UHFFFAOYSA-N 0.000 description 1
- 239000003855 balanced salt solution Substances 0.000 description 1
- 239000007640 basal medium Substances 0.000 description 1
- 210000002469 basement membrane Anatomy 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 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 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 239000012503 blood component Substances 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 239000012888 bovine serum Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 230000008809 cell oxidative stress Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 210000002939 cerumen Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000035606 childbirth Effects 0.000 description 1
- 210000001612 chondrocyte Anatomy 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 238000013170 computed tomography imaging Methods 0.000 description 1
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 1
- 229960000258 corticotropin Drugs 0.000 description 1
- 238000012136 culture method Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- LRCTTYSATZVTRI-UHFFFAOYSA-L cyclohexane-1,2-diamine;platinum(4+);tetradecanoate Chemical compound [Pt+4].NC1CCCCC1N.CCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCC([O-])=O LRCTTYSATZVTRI-UHFFFAOYSA-L 0.000 description 1
- 210000004292 cytoskeleton Anatomy 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 229960002222 dihydrostreptomycin Drugs 0.000 description 1
- ASXBYYWOLISCLQ-HZYVHMACSA-N dihydrostreptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](CO)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O ASXBYYWOLISCLQ-HZYVHMACSA-N 0.000 description 1
- 108010007093 dispase Proteins 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- AVOLMBLBETYQHX-UHFFFAOYSA-N etacrynic acid Chemical compound CCC(=C)C(=O)C1=CC=C(OCC(O)=O)C(Cl)=C1Cl AVOLMBLBETYQHX-UHFFFAOYSA-N 0.000 description 1
- 229960003199 etacrynic acid Drugs 0.000 description 1
- HAPOVYFOVVWLRS-UHFFFAOYSA-N ethosuximide Chemical compound CCC1(C)CC(=O)NC1=O HAPOVYFOVVWLRS-UHFFFAOYSA-N 0.000 description 1
- 229960002767 ethosuximide Drugs 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 210000002266 hair cells auditory Anatomy 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 238000003125 immunofluorescent labeling Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229950008991 lobaplatin Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 208000016848 malignant germ cell tumor Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000000968 medical method and process Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 229960002237 metoprolol Drugs 0.000 description 1
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000007758 minimum essential medium Substances 0.000 description 1
- 229950004962 miriplatin Drugs 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 208000010805 mumps infectious disease Diseases 0.000 description 1
- 229950007221 nedaplatin Drugs 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 208000005923 otitis media with effusion Diseases 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 239000006179 pH buffering agent Substances 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
- 244000052769 pathogen Species 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960002036 phenytoin Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 210000004623 platelet-rich plasma Anatomy 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229960001749 practolol Drugs 0.000 description 1
- DURULFYMVIFBIR-UHFFFAOYSA-N practolol Chemical compound CC(C)NCC(O)COC1=CC=C(NC(C)=O)C=C1 DURULFYMVIFBIR-UHFFFAOYSA-N 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 229940035613 prozac Drugs 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000036299 sexual function Effects 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 230000005236 sound signal Effects 0.000 description 1
- 210000001323 spiral ganglion Anatomy 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 210000000645 stria vascularis Anatomy 0.000 description 1
- 208000023516 stroke disease Diseases 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 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
- 231100000886 tinnitus Toxicity 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 210000003454 tympanic membrane Anatomy 0.000 description 1
- 210000003954 umbilical cord Anatomy 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Classifications
-
- 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
- A61K38/19—Cytokines; Lymphokines; Interferons
-
- 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
- A61K38/30—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- This application relates to the medical use of mesenchymal stem cells, especially the medical use of human skin mesenchymal stem cells in the treatment of hearing disorders.
- the process of auditory perception is basically to first make the sound pass through the auricle of the outer ear, the outer auditory canal to the eardrum, and then to the three ossicles located in the middle ear cavity, and then enter the inner ear through the oval window, and from the inner ear located on the cochlear basement membrane.
- Inner hair cells convert sound signals into nerve signals, which pass through the auditory nerve and brainstem, and finally reach the auditory area of the brain to produce hearing.
- a problem at any point in this path may cause hearing impairment.
- Hearing disorders can be caused by many different causes, including genetic defects, aging, noise damage, pathogenic microbial infections, childbirth complications, ear trauma, drug or poison damage, etc.
- hearing impairment can be divided into five types: (1) Conductive hearing impairment: occurs in the outer or middle ear.
- the causes include cerumen embolism, foreign body, inflammation, tympanic membrane perforation, middle ear effusion, and ossicles.
- Rupture or dislocation, etc. usually belong to mild to moderate hearing impairment, which can be improved by drugs or surgery;
- Sensorineural hearing impairment it occurs in the inner ear or auditory nerve, usually because the auditory hair cells in the cochlea are damaged Or it is caused by lack of it.
- the etiology includes viral infection, ototoxic drug poisoning, aging, noise damage, etc.
- Patients suffering from this type of hearing impairment are usually less sensitive to high-frequency sounds; (3) Mixed hearing impairment, patients are combined Suffering from conductive hearing impairment and sensorineural hearing impairment; (4) Central hearing impairment, which occurs in the central auditory nervous system, and causes include aging, brain injury, neuropathy, etc.; and (5) Functional hearing impairment, patients No organic disease on the auditory canal occurred, but due to psychological or emotional factors, the sensitivity to sound decreased.
- platinum-containing chemotherapeutic drugs are widely used to treat sarcomas, malignant epithelial tumors, lymphoma and germ cell tumors, such as head and neck cancer, brain tumors, ovarian cancer, bladder cancer, and non-small cell lung cancer.
- cisplatin is used (cisplatin; cis-dichlorodiammine platinum (II)) is the most representative.
- a serious side effect of this type of chemotherapeutic drugs is ototoxicity, which significantly reduces the quality of life of cancer patients.
- the ototoxicity of cisplatin mainly occurs in the cochlea and is generally believed to be related to the production of reactive oxygen species.
- Cisplatin is absorbed by stria vascularis, cochlear fluid, and hair cells to enter the cochlea tissue, which activates the third isomer of NADPH oxidase and increases the content of reactive oxygen species in the cochlea.
- endogenous antioxidants such as glutathione
- NF ⁇ B transcription factor
- MSCs Mesenchymal stem cells
- mesenchymal stem cells have the ability of cell proliferation and multidirectional differentiation, and can differentiate into chondrocytes, adipocytes, sclerocytes, etc.
- mesenchymal stem cells have the function of repairing and replacing damaged neurons, they have been actively used in the development of treatments for brain trauma, stroke and neurodegenerative diseases (Hosseini et al., Int J Stem Cells 8:191 -9; and Yoo SW et al., Exp Mol Med 40:387-97).
- mesenchymal stem cells also have the properties of regulating human immune function and reducing cell oxidative stress. Through the action of exocrine microvesicles, it can regulate the imbalance between immune function and oxidative stress in the body.
- mesenchymal stem cells especially human mesenchymal stem cells, such as human skin mesenchymal stem cells, can effectively improve this animal model of hearing impairment.
- the disclosure of this application shows that mesenchymal stem cells can bring beneficial effects on hearing impairment, and can be used as an alternative or supplementary medicine for the treatment of hearing impairment.
- the present invention provides a use of a mesenchymal stem cell composition in the preparation of a medicament for the treatment of hearing disorders in an individual, wherein the mesenchymal stem cell composition comprises mesenchymal stem cells And a pharmaceutically acceptable carrier.
- a method for treating hearing impairment in an individual comprising administering to the individual an effective amount of a mesenchymal stem cell composition; wherein the mesenchymal stem cell composition comprises Mesenchymal stem cells and pharmaceutically acceptable carriers.
- the mesenchymal stem cells are skin mesenchymal stem cells.
- the mesenchymal stem cells are derived from humans.
- the mesenchymal stem cells are human skin mesenchymal stem cells.
- the hearing impairment is selected from sensorineural hearing impairment, mixed hearing impairment and central hearing impairment. In a more preferred embodiment, the hearing impairment is selected from sensorineural hearing impairment.
- the sensorineural hearing impairment is caused by ototoxic drugs.
- the ototoxic drug is selected from platinum-containing chemotherapeutic drugs.
- the platinum-containing chemotherapeutic drug is selected from cisplatin.
- the individual is a human.
- the mesenchymal stem cell composition is prepared as an injection form of a sterile liquid solution or suspension.
- Figure 1 is the process of establishing a mouse model of hearing impairment, showing that cisplatin was injected through the abdominal cavity every day from day 0 to day 5, and human skin mesenchymal stem cells were injected through the tail vein on day 8;
- Figure 2 is a bar graph showing the performance of each group of mouse models in the auditory brainstem response (ABR) test.
- Fig. 3 is a photograph of tissue analysis after immunofluorescence staining, showing the condition of hair cells in the cochlea tissue of each group of mouse models.
- MSCs multipotent stem cells derived from adult stromal tissues. These adult stromal tissues include but are not limited to bone marrow, umbilical cord, amniotic membrane, Amniotic fluid, adipose tissue, pulp cavity, skeletal muscle and skin. MSCs have the ability to self-renew and have the ability to differentiate into cells of the mesenchymal cell lineage.
- the MSC used in this application can be collected from humans, rats, mice, sheep, cows, pigs, dogs, cats, horses, and non-human primates (such as monkeys, gorillas, and chimpanzees).
- the MSCs are derived from humans.
- the MSCs used in this application are isolated from the skin, namely skin mesenchymal stem cells (SMSCs).
- SMSCs skin mesenchymal stem cells
- the skin mesenchymal stem cells are human skin mesenchymal stem cells.
- MSCs from the 1st to 10th generations are usually used, and MSCs from the 2nd to 6th generations are preferably used.
- MSCs can be collected from various sources by methods known in the art, usually stem cells are isolated from tissues. Subsequently, the MSCs were incubated in an appropriate medium for a period of time, and then the supernatant was collected. For example, in the specific example of collecting SMSCs, the skin tissue is first obtained from the skin of the provider through a surgical operation, then the tissue is digested with collagenase, the cell clusters precipitated after centrifugation are washed with phosphate buffer, and then The cells were cultured in a culture medium and other cells were removed to collect SMSCs. In a preferred embodiment, the collection of MSCs can also include isolating MSCs from cell culture by using differences in surface antigen markers.
- Non-limiting examples of isolation methods include magnetic cell sorting (MACS), fluorescence activated cell sorting (FACS), and flow cytometry sorting (FCS). If more than 95% of the collected cells have the three cell surface markers CD90, CD73 and CD105, it can be confirmed that they are human skin mesenchymal stem cells. Subsequently, the collected MSCs are cultured in an appropriate medium for at least 3 hours, preferably 3 to 120 hours, more preferably 24 to 96 hours, for example 72 to 96 hours.
- MCS magnetic cell sorting
- FACS fluorescence activated cell sorting
- FCS flow cytometry sorting
- the medium refers to any liquid medium containing in vitro culture for supporting human or animal cells.
- the medium is a basic medium containing basic nutrients such as inorganic salts, amino acids and vitamins.
- basal media suitable for the present invention include but are not limited to Eagle's Basic Medium (Basal Medium Eagles; BME), Minimum Essential Medium (MEM), Dubbock's Modified Eagle's Medium ( Dulbecco's Modified Eagle's Medium; DMEM), nutrient mixed medium F-10 (HAM's F-10), nutrient mixed medium F-12 (HAM's F-12), or a combination thereof. These media can be easily prepared or purchased from the market.
- the medium is DMEM.
- serum such as serum, plasma, and platelet-rich plasma may be added to the culture medium to support the growth of the cultured cells.
- the medium is supplemented with serum, such as DMEM supplemented with serum.
- serum refers to a liquid preparation derived from human or animal blood, in which blood cells, fibrinogen and fibrin are removed to provide nutrients for cell growth, especially refers to serum preparations derived from humans or animals living in non-epidemic areas, including but not limited to human serum, fetal bovine serum (FBS), calf serum, adult bovine serum or serum from other animals, such as from Serum preparation for horses and camels.
- FBS fetal bovine serum
- calf serum calf serum
- adult bovine serum or serum from other animals such as from Serum preparation for horses and camels.
- the amount of serum in the culture medium is in the range of about 0.5 to 20% by volume based on the total volume of the culture medium.
- the cell culture medium can be further supplemented with other components, such as vitamins, proteins and sugars, growth factors (such as FGF and EGF), antibiotics (such as penicillin, streptomycin, and tetracycline), fungicides, hormones, and antioxidants Wait.
- growth factors such as FGF and EGF
- antibiotics such as penicillin, streptomycin, and tetracycline
- fungicides such as penicillin, streptomycin, and tetracycline
- the term "culture” refers to the maintenance of MSCs under in vitro conditions that are conducive to the growth and survival of MSCs.
- the method of culturing MSCs belongs to the conventional and routine methods in the technical field involved in this application. This application uses standard methods to cultivate MSCs using aseptic processing and manipulation. Generally, the optimum temperature for culture is about 35 to 37°C.
- the cells are cultured in a carbon dioxide incubator.
- the carbon dioxide incubator is usually set at a constant temperature (for example, 37°C), a stable CO 2 level (for example, 5%), a constant pH (for example, pH 7.2-7.4), and a relatively high relative saturation humidity (for example, 95%), To simulate the growth environment of cells in organisms.
- the MSCs culture can be processed by conventional means such as centrifugation or filtration to remove the aqueous part, and then trypsin is used to detach the MSCs from the attached surface, thereby harvesting the cells.
- MSCs especially SMSCs, such as SMSCs derived from human skin tissue
- hearing disorders have the effect of treating hearing disorders.
- hearing impaired generally refers to an individual's decreased sensitivity to sound perception.
- hearing impairment mainly refers to their low sensitivity to the frequency of daily speech.
- WHO World Health Organization
- the severity of hearing impairment can be divided into 4 levels according to the average hearing threshold at four frequencies of 500Hz, 1000Hz, 2000Hz and 4000Hz: 26-40 decibels (dB) It belongs to mild hearing impairment, 41 to 60 decibels are moderate, 61 to 80 decibels are severe, and greater than 80 decibels are depth.
- hearing impairment can be diagnosed through hearing tests. These hearing tests include (1) behavioral or subjective hearing tests, such as pure tone audiometry, tuning fork tests, voice hearing tests, etc.; and (2) physiological or objective tests Hearing tests, such as auditory brainstem response (ABR) test, impedance audiometry, oto-acoustic emissions, etc. Additional tympanic hearing tests, computed tomography and magnetic resonance imaging can also be performed to assist specialists in diagnosis.
- the hearing impairment includes, but is not limited to, conductive hearing impairment, sensorineural hearing impairment, mixed hearing impairment, and central hearing impairment.
- the hearing impairment is selected from the group consisting of sensorineural hearing impairment, mixed hearing impairment and central hearing impairment.
- the hearing disorder is selected from sensorineural hearing disorders, in particular sensorineural hearing disorders involving degeneration, injury or death of hair cells in the cochlea.
- the damage of the hair cells can be evaluated by the histochemical analysis of Example 3 below and/or the audiograms obtained from the above-mentioned hearing examination showing the loss of sensitivity to mid- and high-frequency sounds.
- the hearing impairment is caused by congenital genetic defects of hair cells (such as mitochondrial DNA mutations, OTOF gene mutations), acquired chemical or physical damage (such as ototoxic drug poisoning, noise Injuries), infectious pathogen infections (such as meningitis, mumps, measles, scarlet fever, influenza) or degeneration of senile sexual function (such as insufficient blood supply to hair cells due to vascular sclerosis).
- the hearing impairment is caused by an ototoxic drug.
- ototoxic drug refers to a drug that may cause damage to the outer hair cells and/or inner hair cells in the cochlea after administration, which includes but is not limited to (1) aminoglycoside antibiotics , Such as gentamicin, kanamycin, polymyxin, dihydrostreptomycin, neomycin, etc.; (2) anti-cancer agents, including platinum-containing chemotherapeutic drugs (such as cisplatin, carboplatin (carboplatin) ), nedaplatin, oxaliplatin, lobaplatin and miriplatin), vinblastine anticancer agents, methotrexate, etc.; (3) Antimalarial drugs, such as quinine; (4) diuretics, such as ethacrynic acid, furosemide; (5) steroids, such as corticotropin, prednisone ); (6) Non-steroidal analgesics, such as salicylic acid, diclofenac, and
- the inventor of the present application established an animal model of hearing impairment by administering cisplatin to mice through the ototoxicity of cisplatin.
- the present application evaluated the medical effect of MSCs on hearing impairment by administering MSCs to this animal model.
- the auditory brainstem response test described in Example 2 and the histochemical analysis described in Example 3 below consistently show that the typical symptoms of hearing impairment caused by cisplatin, such as hearing loss and ear hair Cell damage can be improved by administering MSCs. It is worth noting that the administration of ototoxic drugs is selected as a representative hearing impairment trigger mode, because the typical hearing impairment symptoms caused by them also commonly appear in hearing impairments caused by other factors.
- MSCs when MSCs enter the body of patients with hearing impairment, they can secrete a variety of growth factors, cytokines and chemokines, which can enhance cell survival, repair cells, and reduce inflammation. MSCs may also reduce the oxidative pressure of cells by releasing exocrine microvesicles and prevent them from going to apoptosis.
- this application covers the medical use of MSC for the treatment of hearing impairment in an individual, and a method of treating hearing impairment in an individual, the method comprising administering an effective amount of MSC to the individual.
- the term "individual” as used herein is intended to encompass human or non-human vertebrates, such as non-human mammals.
- Non-human mammals include domestic animals, companion animals, laboratory animals, and non-human primates.
- Non-human individuals also include, but are not limited to, horses, cows, pigs, goats, dogs, cats, mice, rats, guinea pigs, gerbils, hamsters, minks, and rabbits. It should be understood that the preferred individuals are humans, especially human patients suffering from or at risk of hearing impairment.
- treatment in this specification means to reverse, alleviate, delay the onset or inhibit the progress of the mood disorders described in this specification or one or more of their symptoms.
- treatment can be performed after one or more symptoms develop. Treatment can also be continued after the symptoms are resolved to delay its recurrence.
- MSCs can be formulated together with a pharmaceutically acceptable carrier to prepare a mesenchymal stem cell composition suitable for administration to an individual.
- a pharmaceutically acceptable carrier as used in this application means an inert substance used as a carrier for MSCs, which has no toxicity, irritation, pyrogenicity, antigenicity, or hemolysis to the site of application, and no The substantial pharmacological activity will not hinder the exertion of the beneficial effects of the MSCs.
- the amount of the pharmaceutically acceptable carrier is from about 1% to about 99.9%, preferably from about 50% to about 99%, based on the total weight of the composition.
- the suitable type of pharmaceutically acceptable carrier depends on the form of the composition.
- MSCs can be administered to an individual by any suitable route.
- the mesenchymal stem cell composition is prepared as an injection, which is in the form of a sterile liquid solution or suspension, to introduce MSCs into an individual's body via veins, arteries, or spinal fluid.
- the pharmaceutically acceptable carrier is isotonic with the blood of the individual.
- Suitable pharmaceutically acceptable carriers include, but are not limited to, water, physiological saline, balanced salt solutions (e.g., phosphate buffered physiological saline (PBS), Hank's balanced salt solution (HBSS)), vegetable oils, dextrose, glycerin , Ethanol, wetting agent, emulsifier and pH buffering agent. In some specific cases, it may be necessary to formulate the composition with a preservative (such as thimerosal or sodium azide) to facilitate long-term storage.
- the carrier may also contain other pharmaceutically acceptable excipients for changing or maintaining the pH, osmolarity, viscosity, transparency, color, sterility, stability, dissolution rate, or odor of the composition.
- the term "administration" includes allocating, delivering, or administering MSCs in a suitable composition to an individual by any suitable route, so as to administer the mesenchymal stem cell composition or its metabolome. It is delivered to the desired location in the individual, so that the composition or its metabolite group is brought into contact with the target cell or tissue.
- the mesenchymal stem cell composition is administered to the individual before, during, and/or after the onset of the emotional disorder.
- one or more therapeutic agents can be administered to the individual together with the mesenchymal stem cell composition.
- the mesenchymal stem cell composition may be administered before the one or more therapeutic agents (e.g.
- the mesenchymal stem cell composition and the therapeutic agent can be administered by different schedules (for example, different plans), different administration routes, or different dosages.
- the mesenchymal stem cell composition is administered to an individual in a therapeutically effective amount to induce the biological or drug response in cells, tissues, systems, animals or humans sought by researchers, veterinarians, doctors or other clinicians, preferably stable , Improve or alleviate one or more symptoms of the disease condition in the individual, such as tinnitus, hair cell death, hearing loss or loss, ear stuffiness, intermittent sound blur, poor or distorted speech recognition, hearing hallucinations , Avoid social interaction, dizziness, and headaches. Therefore, the term "effective amount” refers to the amount of the mesenchymal stem cell composition that produces the medicinal effect of observing any of the above-mentioned symptoms when an effective amount of the composition is administered to an individual.
- the effective amount is usually determined by comparing them with the effect observed in the absence of the mesenchymal stem cell composition disclosed herein (ie, the control group), the actual dose is calculated according to the specific route of administration selected .
- the actual dose can be calculated according to the particular route of administration selected.
- Those skilled in the relevant art will routinely further refine the calculations required to determine the appropriate dosage. Therefore, when administered to a human individual, it is preferably 1 ⁇ 10 4 cells/kg body weight/day to 1 ⁇ 10 7 cells/kg body weight/day per day, weekly or twice a week, for example, 5 ⁇
- the mesenchymal stem cell composition is administered in an amount of 10 5 cells/kg body weight/day to 5 ⁇ 10 6 cells/kg body weight/day.
- the mesenchymal stem cell composition is used for autologous cell therapy, that is, mesenchymal stem cells are obtained from an individual in advance, cultured in vitro, and then transplanted back to the same individual.
- autologous cell therapy that is, mesenchymal stem cells are obtained from an individual in advance, cultured in vitro, and then transplanted back to the same individual.
- autoimmune therapy has relatively few side effects, high safety, and is not prone to allergies and rejection.
- the composition mainly consists of MSCs and the aforementioned pharmaceutically acceptable carrier.
- the "mainly composed of” as used herein means that the described combination of components does not exclude the inclusion of other undescribed components that do not substantially affect the properties and functions of the aforementioned composition.
- the composition of the present application only consists of MSCs and the aforementioned pharmaceutically acceptable carrier.
- the human skin sample was cut into a size of about 3 mm 2 and transferred to an enzyme reaction solution containing neutral protease (dispase) and collagenase, and reacted at 37°C for 16 hours.
- the skin sample fragments and the enzyme reaction solution were transferred to a centrifuge tube, and an equal volume of Dulbecco's modified Eagle's medium (DMEM; Sigma Chemical Co., St. Louis, Missouri, USA) supplemented with an appropriate amount of serum was added for enzyme neutralization. Centrifuge at 1500 rpm for 5 minutes, remove the supernatant, and add DMEM medium containing serum and antibiotics to suspend the cells and move them to a new petri dish, and place them in a carbon dioxide incubator at 37°C for culture.
- DMEM Dulbecco's modified Eagle's medium
- the aqueous part of the skin mesenchymal stem cell culture is removed, and the cells are washed, and then the cells are trypsinized to remove the cells from the culture container, and then the cells are suspended in an aqueous carrier for later use.
- mice 8-week-old C57BL/6 female mice were purchased from Lesco Biotechnology Co., Ltd. (Taipei City). Animals are kept in a sterile environment with automatic 24-hour temperature and humidity control. The room temperature is maintained at 20-22°C, humidity is 50% ⁇ 5%, and the lighting cycle is 12/12 hours day and night. The animals are fed standard rodent feed. As shown in Figure 1, from day 0 to day 5, cisplatin (purchased from Sigma–Aldrich Chemical Co., St. Louis, Missouri, USA) was injected intraperitoneally every day from day 0 to day 5 at a dose of 4 mg/kg mouse body weight to establish Animal model of hearing loss. The control group was intraperitoneally injected with an equal volume of 0.25% dimethyl sulfoxide (DMSO).
- DMSO dimethyl sulfoxide
- the auditory brainstem response (ABR) test was used to evaluate the hearing threshold of each group of animals before the administration of cisplatin on day 0 and on the 15th day, and records were recorded The difference is the threshold offset (in decibels (dB)). The larger the threshold shift value, the more severe the hearing loss caused by cisplatin.
- ketamine 40 mg/kg
- xylazine 10 mg/kg
- ABR workstation BIOPAC Systems
- the ABR waveform is averaged in the interval of 10 milliseconds.
- the sound intensity changes every 10 decibels around the hearing threshold. Based on ABR records, blind analysis was performed by two independent observers.
- Figure 2 is a histogram drawn based on the average values obtained from three independent ABR tests. It shows that the mice in group (III) injected with cisplatin, whether given a series of low-frequency, intermediate-frequency, or high-frequency sound bursts, its The threshold deviation of the ABR test was higher than that of the mice injected with DMSO in group (I), and the statistical analysis reached the significance of p ⁇ 0.05. This indicates that the mice injected with cisplatin showed significant hearing loss compared to the control group, and this application successfully established an animal model of hearing loss.
- mice in each group of Example 1 were anesthetized with isoflurane, and were first perfused with normal saline and then with paraformaldehyde phosphate buffer.
- the cochlear tissue located in the inner ear of the animal was collected and fixed with freshly prepared 4% paraformaldehyde at 4°C for 30 minutes.
- the cochlear tissue was embedded in a frozen tissue embedding agent, and then sliced into a thickness of 10 microns.
- all the sections were incubated with 4',6-diamidino-2-phenylindole, multiple MYO7A antibodies, and phalloidin to display the nucleus of ear hair cells by fluorescent staining. Myosin and cytoskeleton. After washing three times with phosphate buffer, the condition of ear hair cells was observed under a laser conjugate focus microscope (model TCS-SP2; Leica Microsystems Heidelberg GmbH, Heidelberg, Germany).
- Figure 3 shows that the ear hair cells of the mice in the group (III) injected with cisplatin showed obvious defects (as indicated by the arrow) than the ear hair cells of the mice in the group (I) injected with DMSO. This once again points out that this application has successfully established an animal model of hearing loss. Compared with the group (III), the mice (groups (IV) and (V)) that were given MSC preparations through the tail veins had significantly improved ear hair cell defects.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Zoology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Organic Chemistry (AREA)
- Endocrinology (AREA)
Abstract
La présente invention concerne l'utilisation médicale de cellules souches mésenchymateuses, en particulier l'utilisation médicale de cellules souches mésenchymateuses de peau humaine dans le traitement d'une déficience auditive. La déficience auditive comprend, mais n'est pas limitée à, une déficience auditive neurosensorielle, une déficience auditive mixte et une déficience auditive centrale.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/CN2019/111034 WO2021072595A1 (fr) | 2019-10-14 | 2019-10-14 | Utilisation médicale de cellules souches mésenchymateuses dans le traitement d'une déficience auditive |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/CN2019/111034 WO2021072595A1 (fr) | 2019-10-14 | 2019-10-14 | Utilisation médicale de cellules souches mésenchymateuses dans le traitement d'une déficience auditive |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2021072595A1 true WO2021072595A1 (fr) | 2021-04-22 |
Family
ID=75537397
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2019/111034 WO2021072595A1 (fr) | 2019-10-14 | 2019-10-14 | Utilisation médicale de cellules souches mésenchymateuses dans le traitement d'une déficience auditive |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2021072595A1 (fr) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101215546A (zh) * | 2007-12-31 | 2008-07-09 | 浙江大学 | 利用骨髓间充质干细胞诱导获得内耳毛细胞前体的方法 |
CN101878297A (zh) * | 2007-07-05 | 2010-11-03 | 再生科学有限责任公司 | 用于间质干细胞优化扩增和移植的方法与组合物 |
CN104136034A (zh) * | 2011-11-30 | 2014-11-05 | 先进细胞技术公司 | 间充质基质细胞及其相关用途 |
CN106520691A (zh) * | 2016-12-30 | 2017-03-22 | 潍坊医学院 | 一种皮肤间充质干细胞的分离及培养方法 |
US20170189448A1 (en) * | 2013-11-27 | 2017-07-06 | Fundación Pública Andaluza Progreso Y Salud | Novel mesenchymal stem cell surface marker |
-
2019
- 2019-10-14 WO PCT/CN2019/111034 patent/WO2021072595A1/fr active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101878297A (zh) * | 2007-07-05 | 2010-11-03 | 再生科学有限责任公司 | 用于间质干细胞优化扩增和移植的方法与组合物 |
CN101215546A (zh) * | 2007-12-31 | 2008-07-09 | 浙江大学 | 利用骨髓间充质干细胞诱导获得内耳毛细胞前体的方法 |
CN104136034A (zh) * | 2011-11-30 | 2014-11-05 | 先进细胞技术公司 | 间充质基质细胞及其相关用途 |
US20170189448A1 (en) * | 2013-11-27 | 2017-07-06 | Fundación Pública Andaluza Progreso Y Salud | Novel mesenchymal stem cell surface marker |
CN106520691A (zh) * | 2016-12-30 | 2017-03-22 | 潍坊医学院 | 一种皮肤间充质干细胞的分离及培养方法 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR102073730B1 (ko) | 인간 rpe 세포의 생산 방법 및 인간 rpe 세포의 제약 제제 | |
JP2009500297A (ja) | 眼の変性についての細胞療法 | |
JP2010018627A (ja) | 血管の形成ならびに血管新生および栄養因子の生産に使用するための骨髄間質細胞に由来する物質 | |
KR102019277B1 (ko) | 미토콘드리아를 포함하는 허혈성 질환 예방 또는 치료용 조성물 | |
CA2669304A1 (fr) | Utilisation d'une composition comprenant des cellules souches mesenchymales extraites du sang de cordons ombilicaux et provoquant la differentiation et la proliferation de cellules neurales precurseurs ou de cellules souches neurales en cellules neurales | |
JP7014449B2 (ja) | 神経障害を処置するための間葉系細胞由来エキソソーム | |
JP2010504083A (ja) | 血液、特に末梢血から成体幹細胞を増殖させるための方法及び医療分野におけるその利用 | |
JP2013528230A (ja) | ノーオプション重症虚血肢(cli)を処置するための組成物および方法 | |
US20230145213A1 (en) | Pre-conditioned mesenchymal stem cells and preparations and applications thereof | |
JP2001515505A (ja) | 軸索再生を促進する単核貪食細胞及びその使用 | |
Zhang et al. | Reducing host aldose reductase activity promotes neuronal differentiation of transplanted neural stem cells at spinal cord injury sites and facilitates locomotion recovery | |
JP2022502047A (ja) | ヒト網膜前駆細胞の単離および培養の方法 | |
TW200423951A (en) | Method of preparing anti-angiogenic drug from cartilage and chondrocytes and methods of use | |
TW202041222A (zh) | 間質幹細胞在預防和治療情緒疾病上的醫藥用途 | |
WO2021072595A1 (fr) | Utilisation médicale de cellules souches mésenchymateuses dans le traitement d'une déficience auditive | |
Zhou et al. | Neutrophils compromise retinal pigment epithelial barrier integrity | |
Wiranowska et al. | Evaluation of blood-brain barrier permeability and the effect of interferon in mouse glioma model | |
TW202113070A (zh) | 間質幹細胞在治療聽力障礙上的醫藥用途 | |
US20220145248A1 (en) | Use of Adipose-Derived Stem Cells for Glaucoma Treatment | |
CN114099664A (zh) | 一种基于Treg细胞外泌体的靶向协同药物体系及其制备方法 | |
CN107243006B (zh) | Amd3100在制备治疗和/或预防恶液质的药物中的应用 | |
WO2020181411A1 (fr) | Utilisation médicale de cellules souches mésenchymateuses pour prévenir ou traiter des troubles émotionnels | |
TWI690327B (zh) | 西瑞香素於預防組織或器官移植排斥或是移植物抗宿主疾病之用途 | |
US20210353682A1 (en) | Pharmaceutical product for preventing or treating alzheimer's disease | |
US20210244773A1 (en) | Dental pulp stem cells and uses thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 19949411 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 19949411 Country of ref document: EP Kind code of ref document: A1 |