Abstract: PO0644
Treatment of Diabetic NOD/SCID Mice with Human "Neo-Islets," 3D Organoids of Mesenchymal Stromal and Pancreatic Islet Cells, Normalizes Blood Glucose Levels: Significance for Clinical Trials
Session Information
- Development, Stem Cells, and Regenerative Medicine
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Development, Stem Cells, and Regenerative Medicine
- 500 Development, Stem Cells, and Regenerative Medicine
Authors
- Westenfelder, Christof, University of Utah Hospital, Salt Lake City, Utah, United States
- Gooch, Anna, SymbioCellTech, Salt Lake City, Utah, United States
Background
We reported that allogeneic “Neo-Islets” (NI) are immune protected and permanently correct autoimmune diabetes in NOD mice by omental engraftment and endocrine cell redifferentiation. This new “endocrine pancreas” delivers islet hormones physiologically into the hepatic portal vein. Further, treatment of insulin-dependent dogs with allogeneic canine NIs (ongoing FDA-approved Pilot Study) consistently improved glycemic control without the need for antirejection drugs. The current preclinical study was undertaken in anticipation of a Phase 1 Clinical Trial with two objectives: to determine (a) whether human NIs (hNIs) can also restore euglycemia, and (b) whether redosing of suboptimally controlled diabetic animals could restore euglycemia in streptozotocin (STZ)-diabetic NOD/SCID mice, as has been previously shown for mouse and dog cell-derived NIs.
Methods
Passaged cells that were to be used to treat diabetic NOD/SCID mice were characterized for gene expression profiles by rtPCR. For in vivo testing, NOD/SCID mice were made diabetic with STZ, then randomized based on blood glucose levels into groups of 6 each, treated with insulin pellets, and once blood glucose levels were stabilized near normal animals were treated i.p. either with ~2x10e5 human cell-derived NIs/kg bw (n=6) or vehicle (n=6), then followed for 8 weeks. Once blood glucose levels were determined to be no longer significantly improved compared to controls without administration of exogenous insulin, mice in each group were again treated with either 2x10e5 NIs/kg bw or vehicle, and followed for an additional 6 weeks. Therapeutic efficacy was assessed by survival, 2x weekly blood glucose monitoring, and glucose tolerance tests administered 57 and 41 days post the 1st and 2nd doses, respectively.
Results
Human NI therapy significantly improved glycemic control and survival vs. vehicle. A 2nd dose given to the initial group normalized blood glucose levels long-term.
Conclusion
Despite the limitations of the diabetic NOD/SCID model, these data show that human NIs are curative, and in conjunction with data from the dog study, where allogeneic NI therapy reduces the need for insulin without need for antirejection drugs, have high translational relevance and support the planned conduct of human NI clinical trials.
Funding
- Commercial Support – SymbioCellTech