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G gangliosidoses are a family of severe neurodegenerative disorders resulting from a deficiency in the β-hexosaminidase A enzyme. These disorders include Tay-Sachs disease and Sandhoff disease, caused by mutations in the gene and gene, respectively. The and genes are required to produce the α and β subunits of the β-hexosaminidase A enzyme, respectively. Using a Sandhoff disease mouse model, we tested for the first time the potential of a comparatively lower dose (2.04 × 10 vg/kg) of systemically delivered single-stranded adeno-associated virus 9 expressing both human and human cDNA under the control of a single promoter with a P2A-linked bicistronic vector design to correct the neurological phenotype. A bicistronic design allows maximal overexpression and secretion of the Hex A enzyme. Neonatal mice were injected with either this ssAAV9-HexB-P2A-HexA vector or a vehicle solution via the superficial temporal vein. An increase in survival of 56% compared with vehicle-injected controls and biochemical analysis of the brain tissue and serum revealed an increase in enzyme activity and a decrease in brain G ganglioside buildup. This is a proof-of-concept study showing the \"correction efficacy\" of a bicistronic AAV9 vector delivered intravenously for G gangliosidoses. Further studies with higher doses are warranted.

GM2 gangliosidosis disorders are a group of neurodegenerative diseases that result from a functional deficiency of the enzyme β-hexosaminidase A (HexA). HexA consists of an α- and β-subunit; a deficiency in either subunit results in Tay–Sachs Disease (TSD) or Sandhoff Disease (SD), respectively. Viral vector gene transfer is viewed as a potential method of treating these diseases. A recently constructed isoenzyme to HexA, called HexM, has the ability to effectively catabolize GM2 gangliosides in vivo. Previous gene transfer studies have revealed that the scAAV9-HEXM treatment can improve survival in the murine SD model. However, it is speculated that this treatment could elicit an immune response to the carrier capsid and “non-self”-expressed transgene. This study was designed to assess the immunocompetence of TSD and SD mice, and test the immune response to the scAAV9-HEXM gene transfer. HexM vector-treated mice developed a significant anti-HexM T cell response and antibody response. This study confirms that TSD and SD mouse models are immunocompetent, and that gene transfer expression can create an immune response in these mice. These mouse models could be utilized for investigating methods of mitigating immune responses to gene transfer-expressed “non-self” proteins, and potentially improve treatment efficacy.

BackgroundGM2gangliosidosis 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 GM2gangliosides. Mutations in either subunit result in the development of GM2gangliosidosis. The malfunctioning HexA is unable to cleaving GM2ganglioside, 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.ObjectivesThe 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/methodOur 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.ResultsThrough the enzymatic and GM2ganglioside lipid analyses, we see that with a slight increase in enzyme activity, there is a significant increase in the clearance of GM2gangliosides. On behavioural tests, the treated mice outperform their knockout age matched controls. While the untreated controls die by 15 weeks, treated animals survived to x̄=41.77 weeks. The molecular analyses reveal a uniform distribution of the vector in the CNS.ConclusionsThe 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).