880-P: Gene Therapy for MODY3 Moving from Mice to Large Animals

Introduction & Objective: Maturity-onset diabetes of the young type 3 (MODY3) results from mutations in the transcription factor hepatocyte nuclear factor 1A (Hnf1α) gene. We have developed a pancreas-directed adeno-associated viral vectors (AAV)-Hnf1α gene therapy, which counteracted hyperglycemia, improved glucose tolerance and enhanced insulin secretion in MODY3 mice. Here, we further explore the benefits of the AAV-Hnf1α treatment in MODY3 mice and the feasibility of the pancreas-mediated gene transfer in large animals for the future translation of this approach. Methods: AAV-Hnf1α vectors were administered intraductally to MODY3 mice. Biodistribution of vector genomes and Hnf1α expression, and key metabolic parameters were analyzed in these mice. Transcriptomic analysis of islets was also performed. Moreover, healthy beagle dogs were also administered intraductally with AAV vectors, and the AAV biodistribution in the pancreas and other key tissues examined. Results: Treatment of MODY3 mice with AAV-Hnf1α resulted in vector genome copy number in the pancreas but restricted Hnf1α expression to islets. Moreover, comparative transcriptomic analysis in isolated islets revealed the restoration of the MODY3 pathway genes in treated mice. As a first step towards translation, intraductal delivery of AAV vectors to Beagle dog resulted in efficient transduction of pancreas, including endocrine cells, in the absence of adverse events or toxicities. Conclusion: These results provide strong evidence of the efficacy of AAV-Hnf1α to treat MODY3 in mice and pave the way moving to the clinic this approach to treat MODY3 patients in the future.