Gene therapy and long term evaluation of different dietary regimens in a Glycogen Storage Disease Type III KO mouse model

Glycogen storage disease type III (GSDIII) is a rare autosomal recessive disease of glycogen metabolism caused by mutation in AGL gene that encodes the glycogen debranching enzyme (GDE). GDE is the enzyme that breaks down glycogen into glucose in pair with phosphorylase making glucose available for energetic cellular requirements. In GSDIII glycogen accumulates mainly in liver and skeletal muscle and lead to liver impairment in early childhood and muscle damage in adulthood. Pathophysiology of GSDIII is not completely understood and therapies are symptomatic and nutrition based. We have recently developed a knock-out (KO) mouse model for GSDIII that recapitulates the major characteristics of the human disease such as hepatomegaly, glycogen accumulation in liver, skeletal muscle and heart, and muscle impairment. The present project aims to test gene therapy as a therapeutic strategy and to assess the impact of different diets. Our first goal is to test the feasibility of adeno-associated virus (AAV) gene therapy. AAV vectors containing the GDE cDNA will be produced and tested in vitro and in vivo in the mouse. We will define the optimal regimen of treatment and we will evaluate the therapeutic potential of this strategy. We will assess the effects of different nutrient distribution on the phenotype in KO mice. This project will improve the knowledge about the pathomechanisms underlying GSDIII and will contribute to the development of novel therapeutic strategies.