Preclinical characterization of THR to induce pancreatic beta cell regeneration Phase I

The exocrine acinar ductal compartment of the pancreas has been hypothesized to harbor progenitor cells with the ability to give rise to new b cells The activation of such progenitors may potentially result in new b cell formation through differentiation rather than reprogramming We hypothesized that if pancreatic progenitors existed they would respond to bone morphogenetic protein BMP a TGF b family member with dual TGF b inhibition and BMP stimulation abilities This hypothesis was premised on the widely reported link between these two concerted actions and expansion of progenitor pools in multiple tissues Our University of Miami Diabetes Research Institute UM DRI partners have now reported that BMP mediates the in vitro conversion of human non endocrine pancreatic tissue into endocrine cells that are functional both in vitro and in vivo This process entails the activation of progenitor like cells that co express PDX and ALK a BMP receptor Furthermore we have confirmed that THR an ALK agonist cyclic peptide with BMP like activity can induce the same effect and ALK Pdx cells are also present in the mouse pancreas which affords us the possibility of testing the feasibility of endogenous regeneration in a setting not involving transplantation Preliminary data indicate that a daily regimen of THR injections administered to alloxan treated diabetic mice drastically reduces hyperglycemia vs saline treated controls Immunofluorescence analyses of treated mice show small islet like structures with highly increased proliferation rates which are largely absent from saline treated controls Our results are consistent with the hypothesis that THR stimulates the generation of new islets from progenitor like cells a hypothesis that our UM DRI associates are fully dissecting in the context of a parallel project Regardless of the mechanism of action the observed action of THR on b cell formation and enhanced glycemic control warrants the conduct of a project focused on the validation of this small molecule as a therapeutic lead for the induction of b cell regeneration in animal and human tissue models Thus the general objective of this Phase I proposal is to confirm the suitability of THR for clinical development with a single specific aim Confirmation of THR induced b cell regeneration in diabetic mice and live human pancreatic slices In short we will conduct dose dependence and time course studies to confirm our preliminary observations on b cell neogenesis in murine models in vivo as well as in cultured human pancreatic slices a novel analytical tool developed as a collaboration between the Diabetes Research Institute DRI and nPOD Network of Pancreatic Donors with Diabetes that allows for the real time study of the regeneration of b cells within their intact pancreatic niche If successful these studies will seamlessly transition to a Phase II proposal aimed at conducting a full preclinical ADME Tox adsorption distribution metabolism excretion and toxicity and pharmacokinetic PK profile of THR with the goal of submitting an investigational new drug IND application to the Food and Drug Administration FDA The demonstration that resident progenitor like cells within the pancreas can be activated in situ through a simple non genetic intervention could open the door to the design of potentially transformative therapies for diabetes The restoration of insulin producing cell mass is of paramount importance in the development of any effective therapy for type as well as severe cases of type diabetes Cell therapies such as islet transplantation have been successful at reversing hyperglycemia and stem cell based therapies are in the pipeline Achieving the same result through pharmacological means i e via a therapeutic drug regimen would be especially interesting due to their increased translatability into clinical applications We show that THR a small cyclic peptide that mimics the activity of BMP a naturally occurring protein induces the formation of new insulin producing beta cells in diabetic mice This Phase I proposal aims at confirming these results using a variety of rodent and human tissue models with the goal of conducting a thorough preclinical evaluation of THR as a lead candidate for clinical development in Phase II Our research will further our knowledge on human b cell regeneration while speeding up the development of potential therapies for diabetes These studies are highly relevant to the mission of the National Institute of Diabetes and Digestive and Kidney Diseases NIDDK and may ultimately have a significant impact on public health