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MG-110 Intravenous neonatal gene therapy corrects GM2 gangliosidoses in sandhoff mice for ‘long-term’, by using an aav expressing a new hexosaminidase variant
  1. Karlaina JL Osmon1,
  2. Evan Woodley2,
  3. Patrick Thompson3,
  4. Katalina Ong3,
  5. Subha Karumuthil-Melethil4,
  6. Brian Mark5,
  7. Don Mahuran6,7,
  8. Steven J Gray4,8,
  9. Jagdeep S Walia1,2,3
  1. 1Centre for Neuroscience Research, Queen’s University, Kingston, ON, Canada, K7L 3N6
  2. 2Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada, K7L 3N6
  3. 3Medical Genetics/Departments of Pediatrics and Pathology and Molecular Medicine, Queen’s University, Kingston, ON, Canada, K7L 2V7
  4. 4Gene Therapy Centre, University of North Carolina, Chapel Hill, NC, USA
  5. 5Department of Microbiology, University of Manitoba, Winnepeg, Manitoba, Canada, R3T 2N2
  6. 6Genetics and Genome Biology, Sick Kids, Toronto, ON, Canada, M5G 0A4
  7. 7Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, ON, Canada, M5S 1A8
  8. 8Department of Ophthalmology, University of North Carolina, Chapel Hill, NC, USA


Background GM2gangliosidosis 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.

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 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.

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).

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