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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.

Sandhoff disease (SD) is a fatal neurodegenerative disorder belonging to the family of diseases called GM2 Gangliosidosis. There is no curative treatment of SD. The molecular pathogenesis of SD is still unclear though it is clear that the pathology initiates with the build-up of ganglioside followed by microglial activation, inflammation, demyelination and apoptosis, leading to massive neuronal loss. In this article, we explored the expression profile of selected immune and myelination associated transcripts (Wfdc17, Ccl3, Lyz2, Fa2h, Mog and Ugt8a) at 5-, 10- and 16-weeks, representing young, pre-symptomatic and late stages of the SD mice. We found that immune system related genes (Wfdc17, Ccl3, Lyz2) are significantly upregulated by several fold at all ages in Hexb-KO mice relative to Hexb-het mice, while the difference in the expression levels of myelination related genes is not statistically significant. There is an age-dependent significant increase in expression of microglial/pro-inflammatory genes, from 5-weeks to the near humane end-point, i.e., 16-week time point; while the expression of those genes involved in myelination decreases slightly or remains unchanged. Future studies warrant use of new high-throughput gene expression modalities (such as 10X genomics) to delineate the underlying pathogenesis in SD by detecting gene expression changes in specific neuronal cell types and thus, paving the way for rational and precise therapeutic modalities.

Sphingolipids are a specialized group of lipids essential to the composition of the plasma membrane of many cell types; however, they are primarily localized within the nervous system. The amphipathic properties of sphingolipids enable their participation in a variety of intricate metabolic pathways. Sphingoid bases are the building blocks for all sphingolipid derivatives, comprising a complex class of lipids. The biosynthesis and catabolism of these lipids play an integral role in small- and large-scale body functions, including participation in membrane domains and signalling; cell proliferation, death, migration, and invasiveness; inflammation; and central nervous system development. Recently, sphingolipids have become the focus of several fields of research in the medical and biological sciences, as these bioactive lipids have been identified as potent signalling and messenger molecules. Sphingolipids are now being exploited as therapeutic targets for several pathologies. Here we present a comprehensive review of the structure and metabolism of sphingolipids and their many functional roles within the cell. In addition, we highlight the role of sphingolipids in several pathologies, including inflammatory disease, cystic fibrosis, cancer, Alzheimer’s and Parkinson’s disease, and lysosomal storage disorders.