MG-110 Intravenous neonatal gene therapy corrects GM2 gangliosidoses in sandhoff mice for ‘long-term’, by using an aav expressing a new hexosaminidase variant

Abstract

Background G M2 gangliosidosis is a group of neurodegenerative disorders, characterised by the malfunctioning HexosaminidaseA (HexA) enzyme, for which there is no treatment. HexA is composed of two similar, but non-identical subunits, alpha and beta, which interact to hydrolyze G M2 gangliosides. Mutations in either subunit result in the development of G M2 gangliosidosis. The malfunctioning HexA is unable to cleaving G M2 ganglioside, whose accumulation within the neurons of the central nervous system (CNS) is neurotoxic. The resulting neuronal death induces the primary symptoms of the disease; motor impairment, seizures, and sensory impairments. Objectives The aim of this study is to observe the long-term in vivo affects of a novel Hex isoenzyme, HexM treatment in a Sandhoff (beta-deficient) mouse model. Design/method Our methods include intravenous injections of neonatal mice with self-complementary vector expressing HexM at day 0–1. We monitored one cohort for 8 weeks and another cohort long-term for biochemical and behavioural analyses. Results Through the enzymatic and G M2 ganglioside lipid analyses, we see that with a slight increase in enzyme activity, there is a significant increase in the clearance of G M2 gangliosides. On behavioural tests, the treated mice outperform their knockout age matched controls. While the untreated controls die by 15 weeks, treated animals survived to x=41.77 weeks. The molecular analyses reveal a uniform distribution of the vector in the CNS. Conclusions The neonatal delivery of our newly synthesised viral vector expressing HexM to the Sandhoff mice provided long-term correction of the disease. This study will have implications not only for treatment of Sandhoff, but also Tay-Sachs disease (alpha-deficiency).