Зимислецел

Rec. INN (наименование, зарегистрированное ВОЗ)

allogenic pancreatic islets derived from a human embryonic stem cell (ESC) line. The initial ESCs are positive for OCT4A (>70%) and stage-specific embryonic antigen-4 (SSEA4; >90%).
The pancreatic islets are differentiated from the ESCs in five stages: (1) definitive endoderm induction, (2) gut tube formation, (3) early pancreatic progenitor induction, (4) late pancreatic progenitor induction, and (5) pancreatic endocrine induction.
In stage 1 the pluripotent stem cell aggregates are cultured in MCDB-131 serum-free medium supplemented with activin A and 6-[(2-{[4-(2,4-dichlorophenyl)-5-(4-methyl-1H-imidazol-2- yl)pyrimidin-2-yl]amino}ethyl)amino]pyridine-3-carbonitrile (laduviglusib); in stage 2, the cell culture medium is exchanged with medium supplemented with keratinocyte growth factor (KGF); in stage 3 the medium is supplemented with KGF, (1Ξ)-N- (4-benzylpiperazin-1-yl)-1-(3,5-dimethyl-1-phenyl-1H-pyrazol-4- yl)methanimine (SANT-1), (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6- trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenoic acid (tretinoin), phorbol 12,13-dibutyrate (PDBu), N-benzyl-2-[(pyrimidin-4- yl)amino]-1,3-thiazole-4-carboxamide (thiazovivin), 4-(6-{4- [(propan-2-yl)oxy]phenyl}pyrazolo[1,5-a]pyrimidin-3-yl)quinoline (DMH-1), and activin A; in stage 4 the medium is supplemented with KGF, SANT-1, tretinoin, PDBu, thiazovivin, and activin A; and in stage 5 the medium is supplemented with N-(cyclopropylmethyl)-2-[4-(4-methoxybenzoyl)piperidin-1-yl]-N- [(4-oxo-3,5,7,8-tetrahydro-4H-pyrano[4,3-d]pyrimidin-2- yl)methyl]acetamide (NVP-TNKS656), PDBu, SANT-1, betacellulin, (2S)-2-[2-(3,5-difluorophenyl)acetamido]-N-[(3S)-1- methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3- yl]propanamide (γ-secretase inhibitor XXI), low-dose naltrexone (LDN), activin receptor-like kinase 5 (ALK5) inhibitor, glucocorticoid (GC), thiazovivin, staurosporine, 3-deazaneplanocin A (DZNep), tretinoin, and zinc sulfate.
At the end of stage 5 the islet-like aggregates are dissociated into a single cell suspension and cryopreserved. Thawed cells are subsequently reaggregated into islet cell clusters, removing single cells, and then washed before administration. The final substance consists of pancreatic islet β-cells (positive for NK6 homeobox 1 (NKX6.1+) and ISL LIM homeobox 1 (ISL1+)) that synthesize insulin, as well as non-β islet cells (α and δ cell type) and enterochromaffin (EC) cells. There are no detectable residual pluripotent stem cells (OCT 4+/LIN28+)

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