Development Of Novel Diabetes Therapies Based On Neutralizing FSTL3 Activity

Period of Performance: 04/12/2016 - 04/11/2017


Phase 1 SBIR

Recipient Firm

Fairbanks Pharmaceuticals
Principal Investigator


? DESCRIPTION (provided by applicant): Both type 1 and type 2 diabetes involve loss of insulin-producing pancreatic ?-cells resulting in inadequate insulin secretion to control blood glucose. Eventually, daily injections of insulin are required to avoid the constellation of pathologies that arise from 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 far too limited. 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 remainin ?-cells has progressed in rodent studies but has not yet been successfully adapted for human ?-cells. Recently, both human and mouse islet cells have been demonstrated to undergo transdifferentiation to different cell types demonstrating a previously unappreciated flexibility i cell fate. Therefore, expansion of endogenous ?-cell mass through enhancing transdifferentiation of ?-cells into functional ?-cells represents an appealing potential therapetic solution to restoring glucose control. Our prior research has identified the activin signaling pathway and its regulation by a natural antagonist, FSTL3 as having influence on islet cell fate such that loss/inhibition of FSTL3 (FSTL3 KO mouse) results in expansion of ?-cell mass and islet size, resulting in improved glucose regulation. Preliminary results suggests that this ?-cel expansion is due, at least in part, to increased ?- to ?-cell transdifferentiation. Therefore, th long term goal of Fairbanks Pharmaceuticals is to identify antagonists of FSTL3 that will replicate the phenotype of the FSTL3 KO mouse and thus have therapeutic potential. The research proposed here will address the clinical need for new diabetes therapies by developing a series of candidate FSTL3 antagonists that will be screened for antagonist activity, specificity, binding sites, and other characteristics required for a patent application (Specific Aim 1). The net effect of FSTL3 neutralization will be increased activin bioactivity which will be detected using an in vitro bioassay in which luciferase expression is enhanced in the presence of activin signaling. This assay will be used to screen panels of inhibitors to identify the most active candidates. The top ranking antagonists will then be tested for biological function in vitro using human and mouse islets (Specific Aim 2). Together, the two Specific Aims will identify the top 2 to 3 candidate FSTL3 neutralizing compounds that will be tested in vivo in Phase 2 using animal models of diabetes as well as transplanted human islets. Successful FSTL3 antagonists can then be tested in clinical trials for effectiveness in treating diabetes in humans during Phase 3 activities. 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.