Both type 1 and type 2 diabetes involve loss of insulin-producing pancreatic ?-cells resulting in inadequate insulin secretion to control blood glucose, and ultimately requiring daily insulin injections to avoid the constellation of life-threatening complications that arise from long-term hyperglycemia. While transplantation of cadaveric pancreatic islets that contain ? -cells has been successful for treating a small number of type 1 diabetic patients the supply is too limited for the number of type 1 diabetics. Production of functional ?-cells from embryonic stem cells remains an exciting possibility for future treatments but will still involve transplantation with immune protection unless patient-specific ?-cells can be produced. Induction of proliferation in remaining ?-cells has progressed in rodent studies but has not yet been successfully adapted for human ?-cells. Recently, both mouse and human islet cells have been demonstrated to undergo transdifferentiation to different cell types revealing a previously unappreciated flexibility in cell fate. This observation suggests that expansion of endogenous ?-cell mass through enhancing transdifferentiation of ?- cells into functional ?-cells represents an appealing therapeutic solution to restoring glucose control and curing diabetes. Prior research identified the activin signaling pathway and its regulation by a natural antagonist, FSTL3, as having influence on islet cell fate through enhancing ?- to ?-cell transdifferentiation. Our Phase 1 research was directed toward developing FSTL3 antagonist compounds that could block its binding to activin, thereby increasing bioactive activin signaling and enhancing islet function. As demonstrated in the progress report, feasibility of this approach was established and a lead prototype compound generated that could disrupt activin-FSTL3 complexes, was specific for FSTL3, and stimulated glucose mediated insulin release from diabetic islets in vitro. The goal of the proposed Phase 2 research is to demonstrate that FSTL3 neutralization is an effective treatment in vivo and in human islets that can restore glucose homeostasis through enhanced ?- cell regeneration. The top candidate compound from Phase 1 will be tested for restoration of glucose control in mouse models of type 1 and type 2 diabetes as well as in human islets transplanted into mice (Specific Aim 1).
In Specific Aim 2, mouse and human ?-cells will be labeled, treated with the top candidate compound, and ?- to ?-cell transdifferentiation quantitated as a measure of ?-cell regeneration.
Specific Aim 3 will entail humanization of the lead compound along with large scale production and toxicity testing to prepare for large animal and eventual human testing. The long-term goal of this research is to develop a humanized version of our top compound, demonstrate its safety, obtain an IND and test safety and effectiveness of this therapy in phase 1 and 2 clinical trials. The ultimate goal is to produce a transformative diabetes therapy that can increase the number of a patient?s own ?-cells to restore glucose control and thus reduce or eliminate diabetes.
The proposed research is relevant to public health because it addresses the critical issue of developing new treatments for diabetes, a major national health care concern. These patients cannot synthesize sufficient insulin to control blood glucose leading to life-long health complications due to loss of beta cells and our therapy will speed up regeneration of these cells. The Phase 2 research proposed here will capitalize on our Phase 1 progress that established feasibility and in vitro activity of our lead prototype therapy that will be further evaluated in mouse diabetes models.
