Biochemical Correction of GM2 Ganglioside Accumulation in AB-Variant GM2 Gangliosidosis.

Abstract

GM2 gangliosidosis is a group of genetic disorders that result in the accumulation of GM2 ganglioside (GM2) in brain cells, leading to progressive central nervous system (CNS) atrophy and premature death in patients. AB-variant GM2 gangliosidosis (ABGM2) arises from loss-of-function mutations in the GM2 activator protein (GM2AP), which is essential for the breakdown of GM2 in a key catabolic pathway required for CNS lipid homeostasis. In this study, we show that intrathecal delivery of self-complementary adeno-associated virus serotype-9 (scAAV9) harbouring a functional human GM2A transgene (scAAV9.hGM2A) can prevent GM2 accumulation in in GM2AP-deficient mice (Gm2a-/- mice). Additionally, scAAV9.hGM2A efficiently distributes to all tested regions of the CNS within 14 weeks post-injection and remains detectable for the lifespan of these animals (up to 104 weeks). Remarkably, GM2AP expression from the transgene scales with increasing doses of scAAV9.hGM2A (0.5, 1.0 and 2.0 × 1011 vector genomes (vg) per mouse), and this correlates with dose-dependent correction of GM2 accumulation in the brain. No severe adverse events were observed, and comorbidities in treated mice were comparable to those in disease-free cohorts. Lastly, all doses yielded corrective outcomes. These data indicate that scAAV9.hGM2A treatment is relatively non-toxic and tolerable, and biochemically corrects GM2 accumulation in the CNS-the main cause of morbidity and mortality in patients with ABGM2. Importantly, these results constitute proof-of-principle for treating ABGM2 with scAAV9.hGM2A by means of a single intrathecal administration and establish a foundation for future preclinical research.

• Authors: Natalie M Deschenes, Camilyn Cheng, Alex E Ryckman, Brianna M Quinville, Prem Khanal, Melissa Mitchell, Zhilin Chen, Waheed Sangrar, Steven J Gray, Jagdeep S Walia
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 24 Issue 11 (May 24 2023) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 37298170 (Publication Type: Journal Article)

Chemical References

• G(M2) Ganglioside
• G(M2) Activator Protein

Topics

• Humans
• Animals
• Mice
• G(M2) Ganglioside (metabolism)
• Mutation
• Central Nervous System (metabolism)
• Brain (metabolism)
• G(M2) Activator Protein (genetics)
• Gangliosidoses, GM2 (genetics)