In recent studies from our laboratory, we discovered that liver-directed A20-based therapies in mouse models of T1D and T2D, restored or significantly improved glycemic control in ways that fulfilled safety criteria. Bioengineering mouse livers to overexpress A20, led to unexpected reversal of hyperglycemia (i.e., diabetes), or at the very least to significant improvement of glycemic control in diabetic mice. A20, also known as TNFAIP3, is a gene that we showed, over 2 decades ago, to be a critical component of our physiologic anti- inflammatory defense mechanisms1. Previously established effects of A20 in the liver, mostly reported by our group, related to its anti-inflammatory, anti-apoptotic, and pro-regenerative functions, but there was no indication that it could also improve glucose metabolism, until our recent discovery. Mechanistically, we documented that overexpression of A20 in the liver positively impacted local hepatic glucose metabolism, and also systemically improved the regulation of glucose metabolism in other organs and tissues, mostly skeletal muscle. Liver-expressed A20 restored euglycemia and normalized glucose tolerance test (GTT) by decreasing hepatic gluconeogenesis and increasing peripheral glucose uptake. Importantly, A20 restored glycemic control in an insulin-independent manner, and without causing hypoglycemia, even under fasting conditions, including in the NOD mouse model of auto-immune diabetes. Additional benefits of hepatic expression of A20 include A20’s positive impact on lipid metabolism, which led to improved non-alcoholic fatty liver disease (NAFLD) in a mouse model of type II diabetes The case for A20 is further supported by our previously published data showing that physiologic protein levels of endogenous A20, whether in blood vessels or in the liver, are significantly decreased in the presence of high glucose levels i.e. badly controlled diabetes, hence the need to restore its expression through gene therapy in these conditions. We are currently exploring means to develop modified A20 constructs that could resist glucose, and hence reduce the level of gene therapy necessary to achieve glycemic control.

Currently, our goals are geared towards better understanding of the molecular basis for A20’s effects on glycemic control and performing key experiments to facilitate clinical translation of this novel A20-based gene therapy. Specifically, we wish to
1) Characterize the molecular basis that support the ability of liver-expressed A20 to regulates glucose metabolism.
2) Document A20’s effect on glucose uptake, hyperinsulinemic euglycemic clamps, insulin signaling.
3) Optimize AAV-based gene therapies, specifically promoter selection and enhancer elements, to ensure safe and sustained expression of A20 in livers of diabetic animals.
4) Perform pre-clinical toxicology and biodistribution studies in rodents using the optimal AAV-based gene therapy vector identified
5) Engage in additional proof-of-concept studies using a large animal model of T1D, in prelude to clinical implementation.