Converting gut endocrine cells to glucose-responsive insulin-producing cells by selective Foxo1 inhibition to cure insulin-dependent diabetes

In this PhaseproposalForkhead BioTherapeutics IncForkhead Bioaims to demonstrate target validation that selective Foxoinhibitors reprogram gut cells into glucose responsive insulin producinglikecells in vitro and in vivouse a recently established robust assay platform to drive compound optimizationand identify one or more lead molecules with attractive profiles suitable for additional proof of concept studiesOur preliminary data strongly suggest that we re well positioned to complete the proposed work within the funding period and provide key feasibility data to show that chemical inhibitors of Foxocan leverage the body s potential for conversion of gut cells intolike cells to cure typeand treat typediabetesOvermillion patients with typediabetes or late stage typediabetes in the US and EU require lifelong insulin injectionsUnder current treatment paradigmoverof patients with diabetes fail to meet clinical goals of blood glucose managementThis is largely due to the narrow therapeutic window and lifethreatening potential of hypoglycemia of all insulins in clinical useThereforedeveloping therapies that restore or mimic endogenous pancreaticcell functionnamelyreleasing insulin in a glucose regulated mannerremains the holy grail for diabetes researchForkhead Bio s co founder DrDomenico Accili and colleagues made the groundbreaking discovery that ablation of Forkhead box protein OFoxoa transcription factorin the gastrointestinal tract leads to reprogramming of a subpopulation of enteroendocrine cells into insulinpositive cells in mice and in cultured human gut organoidsThe reprogrammed gut cells release insulin only when ambient glucose is high and can restore normal glucose metabolism in a mouse model of insulindeficient diabetesThese findings raise the possibility of an innovative approach by which specific enteroendocrine cells can be converted intolike cells by inhibiting Foxoso that the gut takes over insulin production from the failing pancreaticcells in diabetesWork by Accili et alalso uncovered several series of small molecule chemicals that specifically inhibit Foxoproviding evidence that developing an oral therapy for this target is possibleThese data collectively suggest that this approach has the potential to produce a transformative oral therapy that would radically reduce or even eliminate the need for insulin injections and the burden of frequent blood glucose monitoring through finger pricksthereby significantly improving clinical outcomes and quality of life for patients with diabeteswhile substantially reducing medical costsForkhead Biorecently co founded by DrAcciliDirectorChair of Scientific Advisory BoardCharles QueenanDirectorCEOand DrHua LinCSOhas established strategic collaborations with investigators at the Naomi Berrie Diabetes Center and the Organic Chemistry Collaborative Center at Columbia UniversityIf awardedwork under this SBIR will complement and boost these efforts and substantially accelerate the translation of this promising innovation into an efficacious and patient friendly therapy Overmillion patients in the US and EU with typediabetes or late stage typediabetes require life long insulin therapywhich carries a tremendous personal health burden and staggering economic costsForkhead BioTherapeutics seeks to develop a transformative oral therapy that coverts endogenous gut endocrine cells into glucose responsivelike cells via selective inhibition of FoxOOur innovative technology harnesses the potential of native gut cells to produce insulinthereby replacing chronic insulin injections and achieving normal blood glucose control without the risk of hypoglycemiaeffectively curing insulin dependent diabetes