614-P: Optimal Control of Glucose and Lipid Profiles Is Critical to the Effective “Neo-Islet” Therapy of Insulin Dependent Pet Dogs

Abstract

We demonstrated that ip administration of “Neo-Islets” (NIs; co-aggregation of allogeneic, culture-expanded Islet cells (ICs) with Adipose derived Stem Cells (ASCs)), resulted in their omental engraftment in immune-competent, diabetic NOD mice. This achieved durable euglyciemia without immunosuppression, and with physiologic delivery of insulin and other islet hormones (SCTM 2017;6:1631). We are conducting an FDA guided pilot study (INAD 012-1248) of this technology in spontaneously T1DM pet dogs (see abstract this session). ICs and ASCs are known to be subject to gluco- and lipotoxicity. We undertook this study to determine whether the Hypertriglyceridemic (HTG) and/or DM milieu has an adverse effect (lipotoxic and/or glucotoxic) on dog ASCs and ICs and NIs. Accordingly, serum was collected from HTG, DM dogs enrolled in INAD 012-776 before and after control of HTG and glucose levels, and from non-DM HTG dogs. These sera were added separately (10%) to DMEM at either 5mM or 17mM glucose for dog ASC and IC cultures. Growth rates and gene expression profiles were assessed. Serum from DM (glucose 123-742 mg/dL) dogs with untreated HTG (range 656-1248 mg/dL; normal 20-248 mg/dL) killed ICs at either 5 or 17 mM glucose, and failed to support the expansion of ASCs in 17mM glucose. For ASCs grown in 17mM glucose expression of IL-6 and IGF-1 were downregulated. In contrast, sera from DM dogs with controlled HTG (range 146-656 mg/dL), and serum from HTG (range 742-1114 mg/dL), non-DM dogs supported the growth of both cell types in either medium with no changes in gene expression. In agreement with these in vitro results, an uncontrolled NI-treated study dog failed to respond to therapy, while HTG and glucose-controlled dogs have shown up to 50% reduced need for insulin 12 months post therapy. Conclusion: These data demonstrate the need for optimal glucose and lipid control to prevent destruction of the NI cells when treating DM. Disclosure A. Gooch: Board Member; Self; SymbioCellTech. S.S. Chowdhury: Employee; Self; SymbioCellTech. C. Westenfelder: Consultant; Self; SymbioCellTech.