Development Of Novel Diabetes Therapies Based On Neutralizing FSTL3 Activity

Both typeand typediabetes involve loss of insulin producing pancreaticcells resulting in inadequate insulin secretion to control blood glucoseand ultimately requiring daily insulin injections to avoid the constellation of life threatening complications that arise from long term hyperglycemiaWhile transplantation of cadaveric pancreatic islets that containcells has been successful for treating a small number of typediabetic patients the supply is too limited for the number of typediabeticsProduction of functionalcells from embryonic stem cells remains an exciting possibility for future treatments but will still involve transplantation with immune protection unless patient specificcells can be producedInduction of proliferation in remainingcells has progressed in rodent studies but has not yet been successfully adapted for humancellsRecentlyboth mouse and human islet cells have been demonstrated to undergo transdifferentiation to different cell types revealing a previously unappreciated flexibility in cell fateThis observation suggests that expansion of endogenouscell mass through enhancing transdifferentiation ofcells into functionalcells represents an appealing therapeutic solution to restoring glucose control and curing diabetesPrior research identified the activin signaling pathway and its regulation by a natural antagonistFSTLas having influence on islet cell fate through enhancingtocell transdifferentiationOur Phaseresearch was directed toward developing FSTLantagonist compounds that could block its binding to activinthereby increasing bioactive activin signaling and enhancing islet functionAs demonstrated in the progress reportfeasibility of this approach was established and a lead prototype compound generated that could disrupt activin FSTLcomplexeswas specific for FSTLand stimulated glucose mediated insulin release from diabetic islets in vitroThe goal of the proposed Phaseresearch is to demonstrate that FSTLneutralization is an effective treatment in vivo and in human islets that can restore glucose homeostasis through enhancedcell regenerationThe top candidate compound from Phasewill be tested for restoration of glucose control in mouse models of typeand typediabetes as well as in human islets transplanted into miceSpecific AimIn Specific Aimmouse and humancells will be labeledtreated with the top candidate compoundandtocell transdifferentiation quantitated as a measure ofcell regenerationSpecific Aimwill entail humanization of the lead compound along with large scale production and toxicity testing to prepare for large animal and eventual human testingThe long term goal of this research is to develop a humanized version of our top compounddemonstrate its safetyobtain an IND and test safety and effectiveness of this therapy in phaseandclinical trialsThe ultimate goal is to produce a transformative diabetes therapy that can increase the number of a patient s owncells 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 diabetesa major national health care concernThese 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 cellsThe Phaseresearch proposed here will capitalize on our Phaseprogress that established feasibility and in vitro activity of our lead prototype therapy that will be further evaluated in mouse diabetes models