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US 2023/0056661 A1Published application
Methods and compositions for production of xenogeneic islet cells and treatment of insulin-resistant or -deficient conditions with the same
OwnerYangbin GAO, Yanan YUE +4inventors
InventorsYangbin GAO, Yanan YUE, Luhan YANG, Marc GUELL, Yinan KAN, Wenning QIN
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Abstract
Described here are methods, compositions, and systems for generating transgenic islet cells suitable for xenotransplantation.
Claims42
An isolated transgenic porcine islet cell, wherein said cell:
- (a) is substantially free of enzymatic activity of at least one glycosyltransferase enzyme, wherein said glycosyltransferase enzyme is GGTA, B4GALNT2, or CMAH;
- (b) expresses at least two polypeptide sequences derived from a non-porcine mammalian species, wherein said at least two polypeptide sequences comprise at least two of CD46, CD55, CD59, THBD, TFPI, CD39, B2M, HLAE, CD47, A20, PD-L1, FASL, or HO-1;
- and
- (c) exhibits one or more of the following:
- reduced toxicity from complement derived from said non-porcine mammalian species, reduced induction of activated protein C coagulation derived from said non-porcine mammalian species, reduced induction of thrombin-antithrombin complex derived from said non-porcine mammalian species, or reduced toxicity from NK cells derived from said non-porcine species.
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An isolated transgenic porcine islet cell, wherein said islet cell:
- (a) is substantially free of enzymatic activity of at least two glycosyltransferase enzymes, wherein said glycosyltransferase enzymes comprise at least two of GGTA, B4GALNT2, or CMAH;
- (b) expresses a polypeptide sequence derived from a non-porcine mammalian species, wherein said polypeptide sequence is CD46, CD55, CD59, THBD, TFPI, CD39, B2M, HLAE, CD47, A20, PD-L1, FASL, or HO-1;
- and
- (c) exhibits reduced toxicity from complement derived from said non-porcine mammalian species, reduced induction of activated protein C coagulation derived from said non-porcine species, reduced induction of thrombin-antithrombin complex derived from said non-porcine species, or reduced toxicity from NK T-cells derived from said non-porcine species.
1 more element
The composition of any one of claims 18-20, wherein said composition is prepared according to any one of claims 35-42.
A method of improving yield of islets from a porcine donor prior to transplantation to a non-porcine mammalian recipient, comprising
- (a) providing pancreatic organoids from a neonatal porcine animal that have been subjected to a purification procedure;
- (b) culturing said organoids in the presence of an effective concentration of a caspase inhibitor for at least 90 minutes following said purification;
- and
- (c) continuing culture in the presence of an effective concentration of a corticosteroid for at least 7 days.
1 more element
Dependencies are inferred from the claim text.