AAV9 Gene Therapy in Type II GM1 Gangliosidosis — A Phase 1–2 Trial

BACKGROUND: , 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.).