Preclinical Assessment of Intravenous Gene Therapy for GM2 Gangliosidosis

Abstract

GM2 Gangliosidoses are a group of severe neurodegenerative lysosomal storage disorders characterized by the inability to catabolize GM2 Gangliosides, leading to a neurotoxic accumulation of the GM2 lipids within the central nervous system. The Hexosaminidase A (HexA) enzyme is a heterodimeric protein composed of an α- and a β- subunit, which are coded by the HEXA and HEXB genes respectively. Mutations in either of these genes lead to Tay Sachs Disease and Sandhoff Disease, respectively, through the disruption of the HexA enzyme. These debilitating diseases are fatal by the age of 4 in the infantile version and have no effective treatment available to patients other than palliative care. Herein we assessed the efficacy of two distinct hexosaminidase gene therapy treatment strategies in a Sandhoff mouse model – the ‘hexosaminidase hybrid’ and ‘bicistronic’ vector treatments. We found significant extensions in survival, significant improvements in motor coordination, as well as drastic decrease in the accumulation of the GM2 lipid for both strategies. Specifically, in the assessment of the hexosaminidase hybrid, the low dose cohort and the remaining high dose mice had a significant survival benefit with an average/median survival of 40.6/34.5 and 55.9/56.7 weeks, respectively, over that of untreated controls whose humane endpoint is ~16 weeks. The bicistronic vectors also showed significant improvements in survival, where all vector treatments provided at all ages of administration conveyed improvements in the SD mice in their survival compared to vehicle-treated controls (p<0.001). Mice were treated at 0, 2, 4, and 6 weeks with the human bicistronic vector survived to a median age of 59, 68.4, 43.6, and 43.8 weeks and mice treated with the murine bicistronic vector survived to median age of 42.2, 76.8, 65.8, and 68.14 weeks, respectively. Mice treated with the ssAAV9/mHexb vector only at 0 and 6 weeks and they survived to a median age of 65.72 and 70.71 weeks respectively, with one mouse from the 0-week ssAAV9/mHexb group surviving to the 104-week study endpoint. Significant behavioral, biochemical, and molecular benefit were also observed in both the hybrid and bicistronic strategies. These findings are significant steps forward in the search for a viable treatment for GM2 Gangliosidosis.