Imagine watching your child lose the ability to move and communicate because of a rare, fatal brain disease with no treatment. That's the reality of GM1 gangliosidosis. In a first-of-its-kind trial with nine children, doctors tested a single dose of gene therapy delivered into the bloodstream. The goal was to replace the missing enzyme that causes toxic buildup in the brain. The treatment wasn't easy. All children had elevated liver enzymes that took up to 18 months to return to normal, and one child was hospitalized for severe vomiting linked to the therapy. But there were hopeful signs. The toxic substance in the spinal fluid went down, and the needed enzyme went up. Brain scans suggested the rate of brain shrinkage slowed and there were positive changes in the brain's wiring. While skills like expressive communication and large movements appeared stable, fine motor skills and understanding language still declined. Overall, doctors rated the children as having minimal improvement or no change over 2-3 years, which is notable because without treatment, children with this disease typically get much worse. This early trial shows the therapy engages with the disease and may alter its course, offering a crucial first step for families desperate for options.
Can gene therapy slow a rare, fatal childhood brain disease? Early trial shows some signs it might.
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What this means for you:
An early gene therapy trial showed biochemical promise and slowed some brain changes in a fatal childhood disease, but significant challenges remain. What this means for you:
An early gene therapy trial showed biochemical promise and slowed some brain changes in a fatal childhood disease, but significant challenges remain. View Original Abstract ↓
BACKGROUND: GM1 gangliosidosis, caused by biallelic variants in , results from deficiency of lysosomal β-galactosidase, which degrades GM1 ganglioside. This fatal neurodegenerative disease currently has no effective therapy.
METHODS: In a phase 1-2, open-label, dose-escalation study, we assessed immunosuppression and a single intravenous infusion of adeno-associated virus serotype 9 (AAV9) encoding β-galactosidase in children with type II GM1 gangliosidosis with late-infantile or juvenile onset. The primary end point was safety. Secondary end points included changes from baseline in the cerebrospinal fluid (CSF) GM1 ganglioside concentration and β-galactosidase activity, clinical assessments (including the Clinical Global Impression-Improvement [CGI-I] score, assessed on a scale from 1 [very much improved] to 7 [very much worse]), and neuroimaging patterns.
RESULTS: Nine participants were enrolled. Over a 3-year period, 124 adverse events occurred, 30 of which (8 gastrointestinal events, 21 laboratory abnormalities associated with inflammation, and 1 tachycardia event) were deemed by the investigator as being possibly, probably, or definitely related to the gene therapy. Five serious adverse events occurred, including vomiting that led to hospitalization in one participant, which was attributed to the gene therapy. Serum aspartate and alanine aminotransferase levels increased in all participants and returned to baseline levels by 18 months. In all participants, the CSF β-galactosidase level increased and CSF GM1 ganglioside level decreased. Expressive communication and gross motor scores appeared stable, but fine motor and receptive communication scores decreased. The median CGI-I score was 3 (indicating minimal improvement) at 2 years and 4 (indicating no change) at 3 years; in historical controls, scores have been shown to increase (indicating worsening) over time. Neuroimaging showed patterns consistent with reduced rates of cerebral atrophy and favorable changes in myelination as compared with baseline.
CONCLUSIONS: In this study involving nine participants with type II GM1 gangliosidosis, a single infusion of AAV9 encoding β-galactosidase was associated with adverse events, including severe vomiting in one participant and elevated liver-enzyme levels in all participants. Secondary end-point results suggested improvements in biochemical markers and neuroimaging patterns and stable or reduced rates of developmental deterioration in some measures. (Funded by the National Human Genome Research Institute and others; ClinicalTrials.gov number, NCT03952637.).