FRI604 Stem-cell Derived Islets For Treating Diabetes
Abstract Disclosure: W.L. Rust: Employee; Self; Seraxis Inc. Stock Owner; Self; Seraxis Inc. P.M. Dalal: Employee; Self; Seraxis Inc. Stock Owner; Self; Seraxis Inc. A.P. Koval: Employee; Self; Seraxis Inc. Stock Owner; Self; Seraxis Inc. J.J. Ratiu: Employee; Self; Seraxis Inc. Stock Owner; Self; S...
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| Published in: | Journal of the Endocrine Society Vol. 7; no. Supplement_1 |
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| Main Authors: | , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
US
Oxford University Press
05-10-2023
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| Subjects: | |
| Online Access: | Get full text |
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| Summary: | Abstract
Disclosure: W.L. Rust: Employee; Self; Seraxis Inc. Stock Owner; Self; Seraxis Inc. P.M. Dalal: Employee; Self; Seraxis Inc. Stock Owner; Self; Seraxis Inc. A.P. Koval: Employee; Self; Seraxis Inc. Stock Owner; Self; Seraxis Inc. J.J. Ratiu: Employee; Self; Seraxis Inc. Stock Owner; Self; Seraxis Inc. S.M. Southard: Employee; Self; Seraxis Inc. Stock Owner; Self; Seraxis Inc. P.S. Strumph: Employee; Self; Seraxis Inc. Stock Owner; Self; Seraxis Inc. C.A. Welsch: Employee; Self; Seraxis Inc. Stock Owner; Self; Seraxis Inc.
Background and Aims: We report the development of a novel human multipotent immortal stem cell line, SR1423 that efficiently differentiates to clusters of functional endocrine pancreatic cells. These Synthetic Replacement Endocrine (SRE) clusters contain cell types that recapitulate native islet function in vitro and potently control blood glucose in animal models of type 1 diabetes. Detailed characterization reveals significant distinctions between SRE, native islets and SC-beta cells. SRE clusters are manufactured following GMP requirements in closed vessels with large-scale formats and are being developed for near-term clinical studies. Materials and Methods: SRE was generated by transient expression of the Yamanaka factors in human islet cells harvested from a consented donor pancreas. Rather than screen for pluripotency, this cell line was selected for its ability to differentiate to the definitive endoderm in a first screen, and Pdx1+ pancreatic progenitors in a second screen. SRE does not meet criteria for pluripotency as it fails to express the master control gene for mesoderm specification, brachyury, in response to mesoderm-inducing agents. Comparison against a pluripotent stem cell database demonstrates poor overall differentiation capability for the mesoderm lineage. In contrast, SRE responds to basic differentiation protocols that drive endocrine pancreatic fate choice and generates highly pure populations of cells with endocrine cell characteristics. We therefore characterize SR1423 as a multipotent, and not pluripotent stem cell. In a prospectively designed islet replacement study male NSG mice with streptozotocin-induced diabetes were implanted with SRE clusters to the kidney capsule or gonadal fat pad (as a surrogate for the omentum) and disease progression was monitored. Results: SRE resemble human islets in morphology and distribution of hormone expressing cells. In this mouse model of STZ-induced type 1 diabetes (blood glucose > 180 mg/dL), SRE transplantation resulted in euglycemia 3-4 weeks post-implant; 72 mg/dL +/− 12 SEM when implanted to the kidney capsule (n=13), and 79 mg/dL +/− 15 SEM when implanted to the gonadal fat pad (n=10). Control mice (without SRE implant) in this model of type 1 diabetes (n=2) remained hyperglycemic; 570 mg/dL +/− 20 SEM. Conclusion: These data are consistent with demonstration of proof of principle in this model with resolution of hyperglycemia after transplant of SRE. This is the first description of a novel cell type (non-native, non-SC-beta) with potential clinical therapeutic benefit. SRE clusters are currently in preparation for clinical studies.
Presentation: Friday, June 16, 2023 |
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| ISSN: | 2472-1972 2472-1972 |
| DOI: | 10.1210/jendso/bvad114.828 |