826-P: Treatment of MODY3 Disease by AAV-Hnf1a-Mediated Gene Therapy

Maturity-onset diabetes of the young (MODY) are a group of monogenic diabetes characterized by onset of hyperglycemia at an early adult age, normally before 25 years. MODY3, the most common type of MODY, is caused by mutations in the gene encoding for the transcription factor hepatocyte nuclear factor 1A (HNF1A). MODY3 patients are usually treated with sulfonylureas, but they tend to become unresponsive to these drugs and adverse effects associated to chronic administration of sulfonylureas have been reported. Presently, there are no current treatments addressing the root cause of MODY3. Here, we have developed a new gene therapy approach to treat this disease. To this end, using the CRISPR/Cas9 technology, we first generated a novel MODY3 mouse model that showed pancreatic down-regulation of HNF1A protein production. These mice developed β-cell dysfunction and hyperglycemia, recapitulating the main alterations observed in human patients. Treatment of MODY3 mice by intra-pancreatic duct administration of adeno-associated viral vectors (AAVs) encoding Hnf1α, under control of β-cell-specific promoter, resulted in HNF1A expression in β-cells, which upregulated the expression of HNF1A main target genes, such as GLUT2 and L-PK. AAV-Hnf1α-mediated gene therapy counteracted hyperglycemia, increased insulinemia, improved glucose tolerance and enhanced insulin secretion by pancreatic β-cells, thus reverting the MODY3 disease. This study represents the first demonstration for the genetic counteraction of a monogenic diabetes and paves the way for the clinical translation of AAV-Hnf1α-based gene therapy to treat MODY 3 patients in the future. Moreover, these results may also contribute to the development of new gene therapy strategies for other monogenic forms of diabetes.