883-P: Brain-Directed AAV-FGF21 Gene Therapy Reverses Type 2 Diabetes, Obesity, and Cognitive Decline

Introduction: Type 2 Diabetes (TD2) and obesity are closely related metabolic diseases with an increasing worldwide prevalence. TD2 and obese patients have high risk of developing cognitive decline in the long-term. Fibroblast growth factor 21 (FGF21) has become a promising therapeutic agent for the treatment of obesity and T2D. It has been reported that FGF21 can act in different brain regions to regulate whole body metabolism.

Methods: Two-month-old C57Bl6 mice were fed either a chow or a HFD. Ten weeks later, mice were intra-cerebrospinal fluid (CSF) administered with adeno-associated viral (AAV) vectors encoding FGF21 (AAV-FGF21) and remained in HFD up to 14 months. Body weight, metabolic parameters and behavioral changes were determined at different time points after treatment.

<u></u> Results: Intra-CSF administration of AAV-FGF21 allowed specific overexpression of FGF21 in the CNS, without an increase in FGF21 circulating levels. Brain FGF21 expression resulted in normalization of body weight, adiposity, adipose tissue inflammation and hepatic steatosis and fibrosis. Moreover, AAV-FGF21 treatment counteracted HFD-induced insulin resistance, glucose intolerance and islet hyperplasia. This was parallel to enhanced energy expenditure resulting from FGF21 signaling in the CNS. Moreover, brain FGF21 expression also counteracted obesity-associated cognitive decline, prevented short-term and long-term memory loss, improved learning capacity and decreased anxiety-like behavior.

Conclusion: All these results underscore the potential of brain-directed AAV-FGF21 gene therapy to treat obesity, insulin resistance, T2D, and associated cognitive decline.