2026-07-12 | Extracellular vesicles from inflammatory-primed stromal cells reduce in vitro inflammation in Sandhoff disease model.
Sandhoff disease (SD) is a fatal lysosomal storage disorder caused by β-N-acetylhexosaminidase deficiency, resulting in GM2 ganglioside accumulation, severe neurodegeneration, and chronic neuroinflammation. While enzyme-restoring therapies, such as AAV gene transfer, effectively target the primary enzymatic deficit, neuroinflammation persists and contributes to disease progression, motivating the development of anti-inflammatory adjuncts alongside disease-modifying interventions. Extracellular vesicles released by mesenchymal stromal cells (MSC-EVs) are acellular lipid nanoparticles that contain immunomodulatory molecules and can cross physical barriers, without immunogenicity issues. These features make MSC-EVs promising candidates for anti-inflammatory therapeutics targeting neuropathology. The anti-inflammatory potency of MSC-EVs is increased by priming parent MSCs with pro-inflammatory cytokines, resulting in IFEVs, as referred to in this study. Here, we evaluated the in vitro anti-inflammatory effects of IFEVs in a feline model of SD. IFEVs reduced SD neuroinflammation, lowering IL-6, TNF-α, and IL-1β protein levels in SD neuronal-mixed glia, with concordant transcriptional downregulation of NF-κB/p65 and NLRP3 components and upregulation of arginase 1 mRNA after 48 h of treatment. In SD peripheral blood mononuclear cells, IFEVs significantly increased the proportion of regulatory T cells and the Treg/T-effector cell ratio without inducing cytotoxicity. Together, these findings demonstrate that IFEVs reduced neuroinflammation and altered blood-circulating T-cell populations in an in vitro SD model, supporting their further preclinical development as a complementary immunomodulatory therapy for SD.
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2026-05-20 | Sinbaglustat is efficacious in GM2 gangliosidosis primarily through inhibition of GBA2 rather than GCS.
Sinbaglustat is a brain-penetrant iminosugar under clinical investigation for glycosphingolipid (GSL) storage disorders, including GM2 gangliosidosis. It inhibits non-lysosomal glucosylceramidase (GBA2) with higher potency than glucosylceramide synthase (GCS). While efficacy of related GBA2/GCS inhibitors in mouse models of Sandhoff disease was previously demonstrated, the specific contribution of GBA2 inhibition to therapeutic outcome has remained unclear. We dissected the mechanism of Sinbaglustat in Sandhoff Hexb -/- mice using 30 or 300 mg/kg/day doses, designed to preferentially inhibit GBA2 alone or both GBA2 and GCS, respectively. Sinbaglustat's dose-dependent effects on GSLs in relation to both drug targets were consistent across enzymatic assays, patient-derived cells, and wild-type mouse brain. In Hexb -/- mice, GBA2 inhibition alone was sufficient to alter central GSL metabolism, attenuate neuroinflammatory gene expression, delay onset of motor symptoms by ≥ 2 weeks, and extend survival by 15%. High-dose treatment broadened substrate clearance via GCS inhibition and extended survival by 22%. These results reveal a therapeutic role of GBA2 inhibition in the brain and highlight sinbaglustat, an iminosugar without gastrointestinal side effects, as a promising candidate for GM2 gangliosidosis. By defining the mechanistic contribution of its dual targets, this study offers insight for dose optimization and therapeutic design in lysosomal storage disorders.
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2026-01-08 | Therapeutic Effects of Nizubaglustat in a Mouse Model of GM2 Gangliosidosis.
Nizubaglustat is a novel selective inhibitor of glucosylceramide synthase (GCS) and the non-lysosomal glucocerebrosidase (NLGase, GbA2) with brain penetrant properties. It is currently in clinical development as an oral treatment for rare lysosomal storage diseases with neurological involvement. One such disease group called GM2 gangliosidosis, to date, has no approved therapeutic treatment. To test the potential efficacy of nizubaglustat in a mouse model of GM2 gangliosidoses, we treated Sandhoff disease (SD) mice carrying a homozygous null mutation in the Hexb gene, as well as healthy heterozygous controls, to understand exposure versus effect under disease conditions. Oral doses of nizubaglustat from 0.2 to 6 mg/kg/day showed linear pharmacokinetics with plasma and brain concentrations sufficient to drive pharmacodynamic changes in markers of target engagement and efficacy. In the brain, an approximately 10-fold increase in GlcCer C16:0 and C18:0 was observed, which is consistent with NLGase inhibition. A statistically significant increase in survival (22%) was noted in SD mice treated at doses as low as 0.2 mg/kg/day compared to controls. Behavioral analyses, which included rotarod and open field tests, were also significantly improved. To understand the added potential mechanism of the improved survival, a subset of neuroinflammatory markers was also examined in specific brain regions. Gene expression studies showed an anti-inflammatory pattern with downregulation of Itgax, Trem2, Cxcl10 genes as an example. Brain immunohistochemistry for GFAP was decreased compared to vehicle treated control animals. These results provide proof-of-concept that nizubaglustat can be a promising therapeutic drug to treat patients with GM2 gangliosidoses.
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