1: Center for Animal Biotechnology and 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. Among them, MODY3, the most common type of MODY, is caused by mutations in the gene encoding for the transcription factor hepatocyte nuclear factor 1A (HNF1A). Here, using a unique novel strategy based on the CRISPR/Cas9 technology, we generated the first MODY3 mouse model that presented beta-cell dysfunction and diabetes, faithfully mimicking the human clinical phenotype. MODY3 mice treated with AAV vectors encoding HNF1A showed markedly increased HNF1A protein content and upregulation of HNF1A target genes in islets, that resulted in counteraction of hyperglycemia. This study constitutes the first demonstration of genetic treatment for a monogenic diabetes and paves the way to clinical translation to MODY3 patients in the future.