Pancreatic gene therapy durably improves glycaemia and delays disease progression in a murine model of type 2 diabetes

Beta-cell (β-cell) failure is a root cause of the progression of type 2 diabetes (T2D). GLP-1 receptor agonists (GLP1RA) have proven clinical efficacy and improve β-cell function. However, systemic side effects limit patient adherence and long-term efficacy. Localized pancreatic GLP1RA production may engender durable islet cell benefit while diminishing side effects. We developed a novel adeno-associated virus (AAV) gene therapy delivery platform to enable local and durable production of therapeutic proteins by the pancreas. We assessed to what degree a β-cell restricted GLP1RA gene therapy impacts disease progression in the db/db mouse compared to semaglutide (Sema). To establish a baseline for chronically administered systemic GLP1RA, Sema (10 nmol/kg) or vehicle were given daily to 5-week-old mice for 10 weeks (n=8/group). Sema treated mice had a 64% decrease in fasting blood glucose (FBG; p<0.0001) and a 3.5-fold increase in fasting insulin (FI; p=0.01) across the time course. Glucose tolerance was significantly improved during IPGTT at weeks 3, 6, and 9 (p<0.001). To determine the impact of a single dose GLP1RA gene therapy, 1) β-cell restricted AAV-GLP1RA, 2) AAV control, or 3) vehicle were given to 5-week-old mice (n=8/group). Remarkably, AAV-GLP1RA treatment decreased FBG levels by 70% (p<0.0001) and elevated FI by 1.9-fold (p<0.01) compared to controls for 10 weeks. Glucose tolerance was improved during IPGTT at weeks 3, 5, 7, and 9 (p<0.01). AAV-GLP1RA protein was undetectable in serum and restricted to the islet, suggesting improved glycemic control was due to intra-islet GLP1RA production and signaling. These results demonstrate that a single dose β-cell restricted GLP1RA gene therapy can comparably improve glycemia and delay disease progression in a murine model of T2D when compared to chronic systemic GLP1RA administration. These data provide proof of concept that a gene therapy has the potential to durably treat metabolic diseases, including T2D. Disclosure A.L.Fitzpatrick: Employee; Fractyl Health, Inc. E.Cozzi: Employee; Fractyl Health, Inc. J.Wainer: Employee; Fractyl Health, Inc. R.Reese: Employee; Fractyl Health, Inc. N.Khanna: Employee; Fractyl Health, Inc. J.Caplan: Employee; Fractyl Health, Inc. H.Rajagopalan: Employee; Fractyl Health, Inc. J.A.West: Employee; Fractyl Health, Inc. Funding Fractyl Health, Inc.