DELIVERY OF A scAAV9.coGM2A FOR PHENOTYPIC CORRECTION OF GM2 GANGLIOSIDOSIS AB-VARIANT, IN THE NEWLY CHARACTERIZED GM2A/NEU3 DOUBLE KNOCKOUT MOUSE MODEL

Abstract

AB-Variant GM2 gangliosidosis (ABGM2) is an autosomal recessive lysosomal lipid storage disorder characterized by an overaccumulation of GM2 gangliosides in neuronal lysosomes, ultimately resulting in neuronal cell death. This disorder arises due to a mutation in the GM2A gene, which encodes for GM2 Activator Protein (GM2AP), an essential cofactor in the hydrolysis of GM2 gangliosides. Overaccumulation of GM2 gangliosides and eventual neuronal cell death present as phenotypic symptoms of sensory, motor, and cognitive decline and ultimately result in a shortened lifespan. In its most severe and common infantile form, death can occur as early as 4 years of age. Currently, there are no curative treatments available for ABGM2. The delivery of a gene therapy using an Adeno-Associated Virus expressing a codon-optimized human GM2A transgene was proposed to treat ABGM2. Previous studies utilizing GM2A transgene administration in Gm2a-/- murine models showed reduction in GM2 ganglioside accumulation as well as widespread vector biodistribution to the central nervous system; however, this model does not accurately mirror the severe human form due to its normal lifespan. This has led to the creation and characterization of a Gm2a-/-/Neu3-/- murine model, which more closely parallels the symptoms and lifespan of the severe human form of ABGM2. The purpose of the present study was to investigate the dose-response relationship of intrathecal delivery of scAAV9.coGM2A (low 0.4e11vg/mouse, medium 0.8e11vg/mouse, or high 1.6e11vg/mouse) on GM2 ganglioside accumulation, behavioural parameters and mortality in the newly characterized Gm2a-/-/Neu3-/- murine model. Overall, the data suggests a dose response effect on GM2 ganglioside accumulation, with the high dose demonstrating the greatest reduction of 1.9-fold (p=0.0007, ***). Furthermore, all dosages produced improvements in behavioural parameters and significant improvement in survival of as high as 1.5-fold. These results contribute to the evidence for the potential clinical efficacy and safety of scAAV9.coGM2A in the treatment of ABGM2.