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.

Open article ↗

2026-06-18 | The RAINBOW study: a phase 2 trial evaluating the 3-month pharmacokinetic and pharmacodynamic data and 18-month clinical and safety outcomes of nizubaglustat in GM2 gangliosidoses or Niemann-Pick type C disease.

GM2 gangliosidoses and Niemann-Pick type C disease (NPC) belong to a group of rare, progressive neurodegenerative lysosomal diseases that cause diverse neurological symptoms. Disease-modifying therapies exist for NPC, but not for GM2 gangliosidoses. Nizubaglustat is in development for both conditions. In RAINBOW, a phase 2, double-blind, placebo-controlled multicenter trial, participants with GM2 gangliosidoses or NPC were randomized 1:1:1 to receive once-daily nizubaglustat 3 mg, nizubaglustat 9 mg, or placebo for 12 weeks, after which participants could enter a double-blind extension period and receive nizubaglustat 3 mg or 9 mg. Primary outcomes were plasma pharmacokinetics, pharmacodynamics, and the safety of nizubaglustat over 12 weeks. Clinical outcomes included changes from baseline in Scale for the Assessment and Rating of Ataxia (SARA), functional SARA scores, and Inventory on Non-Ataxia Signs (INAS) count during the extension; these outcomes were evaluated separately from the double-blind, placebo-controlled analyses at 12 weeks. Among 13 participants (GM2 gangliosidoses [n = 7], NPC [n = 6]; mean age, 18.6 years; 53.8% male), nizubaglustat demonstrated rapid absorption accompanied by dose-dependent reductions in plasma C16/C18 glucosylceramides. Most adverse events were mild to moderate and manageable. Pharmacokinetics, safety, and tolerability data established an optimal nizubaglustat dose (9 mg, adjusted for weight). During the extension (n = 11), 45.5% of participants had improved by ≥1 point or stabilized in SARA, 54.6% in functional SARA, and 63.7% in INAS; seizure frequencies were reduced from baseline. Nizubaglustat demonstrated a favorable safety profile and potential clinical benefits by reducing disease progression and seizure burden in participants with GM2 gangliosidoses or NPC, supporting advancement to a phase 3 trial in a larger cohort.

Open article ↗

2026-06-10 | An example for potentially underrated causes of recessive disease in the Greater Middle East: integrative long-read genome and transcriptome sequencing pinpoint a deep-intronic homozygous HEXB candidate founder variant in GM2-gangliosidosis

Abstract Background Consanguinity provides shortcuts to identify homozygous recessive mutations. However, deep-intronic variants escape standard sequencing (panel; exome/WES), and their pathogenicity cannot be inferred from genomic data. We applied WES, long-read genome and long-read-RNA-sequencing (LR-WGS, LR-RNA-Seq) in a Syrian patient with biochemically evident GM2-gangliosidosis. Results No exonic HEXA, HEXB and GM2A mutations were found. LR-WGS/LR-RNA-Seq revealed a homozygous HEXB variant, c.771 + 985G > A, activating a 97 bp pseudo-exon. Conclusions Integrative genome and transcriptome sequencing unlocked a deep-intronic, database-annotated HEXB mutation and proved causality. This illustrates the diagnostic challenges in patients from the Middle East with its prevalent consanguinity and hidden (candidate founder) mutations which are potential targets for splice-modulating therapies.

Open article ↗

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.

Open article ↗

2026-04-28 | HEXA Enzyme Replacement for GM2 Gangliosidosis-Related Dementia

HEXA encodes beta-hexosaminidase A, deficiency of which causes GM2 ganglioside accumulation leading to neurodegeneration and dementia. ChEMBL compounds CHEMBL4861823 (pChEMBL: 6.69) and CHEMBL4874886 (pChEMBL: 6.90) target HEXA. These compounds could potentially enhance residual enzyme activity or serve as pharmacological chaperones.

Open article ↗