AAV9-GLB1 Gene Therapy Shows Manageable Safety Profile and Potential Disease Stabilization in GM1 Gangliosidosis

A single intravenous infusion of AAV9-GLB1, an adeno-associated virus serotype 9 (AAV9) gene therapy encoding beta-galactosidase, demonstrated a manageable safety profile and signals of delayed disease progression in children with type II GM1 gangliosidosis, according to Phase I/II data published in The New England Journal of Medicine.

The open-label trial enrolled nine pediatric patients (ages 6 months to 12 years) with biallelic GLB1 variants and confirmed beta-galactosidase deficiency. Participants received a one-time intravenous infusion of AAV9-GLB1 at either 1.5×10¹³ or 4.5×10¹³ vector genomes/kg, with safety assessed over three years.

Over the 3-year follow-up, 124 adverse events were reported. Thirty events were considered at least possibly related to the AAV9 gene therapy, including inflammatory laboratory abnormalities, gastrointestinal symptoms, and one tachycardia event.

Five serious adverse events occurred; one case of vomiting was attributed to treatment and required hospitalization. Elevated liver enzymes (AST and ALT) were observed in all participants but returned to baseline by 18 months. Importantly, no cases of thrombotic microangiopathy, hemophagocytic lymphohistiocytosis, or acute respiratory distress syndrome were reported—complications previously associated with higher-dose AAV therapies.

Treatment with AAV9-GLB1 increased cerebrospinal fluid (CSF) beta-galactosidase levels and reduced CSF GM1 ganglioside levels in all participants, indicating biochemical target engagement.

Clinical assessments showed stable expressive communication and gross motor function, while fine motor and receptive communication scores declined. Neuroimaging suggested reduced rates of cerebral atrophy and favorable myelination changes.

At two years, the median Clinical Global Impression-Improvement (CGI-I) score was 3 (minimal improvement). At three years, the median score was 4 (no change). Given the progressive and fatal nature of untreated GM1 gangliosidosis, investigators noted that disease stabilization over three years may represent clinically meaningful benefit.

GM1 gangliosidosis is a rare, inherited lysosomal storage disorder caused by biallelic mutations in GLB1, leading to beta-galactosidase deficiency and toxic accumulation of GM1 ganglioside in neurons. Type II disease typically presents in late infancy or childhood and is marked by neurodegeneration, developmental regression, and limited life expectancy. There are currently no approved disease-modifying treatments.

Preclinical studies in feline models demonstrated that intravenous AAV9-GLB1 improved survival and enzyme activity without tumorigenesis or significant toxicity, supporting clinical translation.

While dose-dependent responses were not clearly observed across clinical or imaging endpoints, the study provides preliminary evidence that single-dose systemic AAV9-mediated gene therapy can achieve sustained biochemical correction with acceptable safety over three years.

The authors conclude that earlier intervention and longer-term follow-up will be critical to fully define the therapeutic potential of AAV9-GLB1 in GM1 gangliosidosis.