A Phase 1/2 Study of Intravenous Gene Transfer With an AAV9 Vector Expressing Human Beta-galactosidase in Type I and Type II GM1 Gangliosidosis

This is a non-randomized, Phase 1/2 clinical trial to study the safety and efficacy of a single dose gene transfer vector AAV9/GLB1 (AAV9-GLB1) by intravenous infusion to subjects with Type I and Type II GM1 gangliosidosis.

Type I subjects in this study will be male and female, >= 6 months old and <=12 months of age at the time of full ICF signing, with a diagnosis of Type I GM1 gangliosidosis. Type II subjects in this study will be male and female, > 6 months old and < 12 years old at the time of full ICF signing, with a diagnosis of Type II GM1 gangliosidosis. The subjects must have biallelic mutations in GLB1, a deficiency of Beta-galactosidase enzyme documented by testing in a CLIA-certified clinical laboratory, and serum AAV9 antibodies titers <= 1:50). Other inclusion/exclusion criteria apply. In Stage 1, up to 5 Type II subjects will receive 1.5E13 vg/kg of the gene transfer agent, and up to 4 Type II subjects will receive 4.5E13 vg/kg of the gene transfer agent. In Stage 1, up to 3 Type I subjects will receive 1.5E13 of the gene transfer agent (Cohort 1) and up to 3 will then receive 4.5E13 of the gene transfer agent (Cohort 2). Dosing will be staggered to ensure subject safety.

Following the last Stage 1 subject s 6 months visit, data will be reviewed, and Stage 2 dosing will be determined. Up to 12 Type II and 6 Type I subjects are planned to be treated in Stage 2 of the study. If Stage 2 dosing is to proceed, it will be reflected in a protocol amendment.

The primary objective of Stage 1 of the study is to assess the safety of the AAV9-GLB1 vector following intravenous infusion. Stage 1 secondary and exploratory objectives include assessment of gene therapy on disease biomarkers, neurologic development and motor function, brain volume and myelination, and immune tolerance to the gene transfer vector.

Stage 2 of the study will assess the safety and efficacy of AAV9-GLB1 vector following intravenous infusion of the dose selected based on data from both Type I and II subjects.

Type I and Type II subjects have differing disease progression and symptomatology, justifying distinct endpoints and timepoint measures.

GM1 gangliosidosis is an autosomal recessive, neurodegenerative lysosomal storage disorder resulting from mutations in the GLB1 gene, encoding the enzyme Beta-galactosidase (Betagal). Betagal functions by removing terminal galactose moieties from GM1 ganglioside, a glycosphingolipid present in highest quantity in the CNS, primarily found in neurons. Betagal deficiency leads to accumulation of GM1 ganglioside and its asialo derivative (GA1) in the CNS. The age of onset and progression of GM1 gangliosidosis differs depending on the amount of residual Betagal activity, but the disease is generally divided into three clinical forms: Type I (infantile), Type IIa and IIb (late-infantile and juvenile), and Type III (adult or chronic). This clinical trial will treat GM1 Type I and Type II subjects.

The Type I form is the most severe, with age of onset less than 12 months of age and death often before age 3. Clinical findings of hypotonia and developmental delay/regression are found in almost all patients. In addition to symptoms resulting from severe CNS degeneration, evidenced by the presence of cherry-red maculae, infants often exhibit peripheral signs, including hepatosplenomegaly, skeletal dysplasia, cardiomyopathy, and coarse facial features.

The Type II form of GM1 generally has onset between 3 and 5 years with plateauing, then regression of developmental milestones (juvenile) or onset of symptoms after 12 months but before 24 months, plateauing of milestones then regression (late infantile).

Clinical features vary but in addition to CNS manifestations typically include a degree of skeletal involvement and mild hepatosplenomegaly. The primary symptoms are frequent falls, poor coordination, dysarthria and cognitive decline. Disease progression is variable, with subjects surviving well into the third decade (juvenile) or into the late teens (late infantile), but with severe cognitive and physical disabilities.

GM1 gangliosidosis is extremely rare, with an incidence estimated at 1:100,000 to 1:200,000. The disease is uniformly fatal with no effective therapy. Care is limited to symptomatic medical management. Intravenous administration of a gene transfer vector to deliver a normal copy of the GLB1 gene to the CNS could potentially provide an effective treatment for GM1 gangliosidosis.