Background:

GM1 gangliosidosis is a disorder that destroys nerve cells. It is fatal. There is no treatment. People with GM1 are deficient in a certain enzyme. A gene therapy may help the body make this enzyme. This could improve GM1 symptoms.

Objective:

To test if a gene therapy helps Type I and Type II GM1 gangliosidosis symptoms.

Eligibility:

Type I subjects will be male and female >= 6 months <= 12 months of age at the time of full ICF signing.

Type II subjects will be male and female > 12 months old and < 12 years old at the time of full ICF signing.

Design:

Participants will be screened with their medical history and a phone survey.

Participants will stay at NIH for 8-10 weeks.

Participants will have baseline tests:

Blood, urine, and heart tests

Hearing tests

Ultrasound of abdomen

EEG: Sticky patches on the participant s head will measure brain function.

Lumbar puncture: A needle will be stuck into the participant s spine to remove fluid.

MRI scans, bone x-rays, and bone scans: Participants will lie in a machine that takes pictures of the body

IQ tests

Neurology exams

Central line placement

Skin biopsy: A small piece of the participant s skin will be removed.

Speech tests

Participants will have an x-ray while swallowing food.

Participants will take drugs by mouth and IV. This will get their immune system ready for therapy.

Participants will get the gene therapy by IV. They may stay at NIH for a week to watch for side effects.

Participants will have visits 3 and 6 months after treatment. Then visits will be every 6 months for 2 years. Then they will have a visit at 3 years. Visits will take 4-5 days.

Participants will return to NIH once a year for 2 years for tests in an extension study....

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 6 Type II subjects will receive 1.5E13 vg/kg of the gene transfer agent, and up to 6 Type II subjects will receive 4.5E13 vg/kg, and up to 6 Type II subjects will recieve 7.5E13 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.

• INCLUSION CRITERIA:

Type I subjects

• Male or female subjects >= 6 months old and <= 12 months old at time of full ICF signing

• Biallelic mutations in GLB1

• Documented deficiency of Beta-galactosidase enzyme by clinical laboratory testing

• Phenotype consistent with a diagnosis of Type I GM1 gangliosidosis

  • Symptomatic subjects: as determined by the opinion of the Principal Investigator and based on the criteria set forth by Brunetti-Pierri et al:

    • Age of symptom onset <= 6 months of age
    • Rapidly progressive with developmental delay and hypotonia

  • Pre- symptomatic subjects: must have mutations confirmed to be associated with the Type I subtype

• AAV9 antibody titers <=1:50

• Agree to reside within 50 miles of the study site for at least 1 month following treatment

Type II subjects

• Vineland-3 Adaptive Behavior composite standard score greater than or equal to 40
• Male or female subjects > 6 months old and < 12 years old at time of full ICF signing
• Biallelic mutations in GLB1
• Documented deficiency of beta-galactosidase enzyme by clinical laboratory testing
• Phenotype consistent with a diagnosis of Type II GM1 gangliosidosis, with symptom onset after the first year of life
• AAV9 antibody titers <=1:50
• Agree to reside within 50 miles of the study site for at least 1 month following treatment

EXCLUSION CRITERIA:

• AAV9 antibody titers >1:50

• Contraindications to concomitant medications

• Serious illness that would not allow travel to the study site

• Unwilling to undergo study interventions as outlined in the Schedule of Events

• Subjects receiving other unapproved, off-label or experimental therapies for GM1 gangliosidosis (i.e. miglustat, Tanganil) within the last 60 days

• Any prior participation in a study in which a gene therapy vector or stem cell transplantation was administered

• Pregnant or lactating subjects

• Immunizations of any kind in the month prior to screening

• Evidence of cardiomyopathy on history, exam, or additional testing (echocardiogram or electrocardiogram) or other cardiac disease that in the opinion of the investigator would deem the subject unsafe to participate in the trial

• Indwelling ferromagnetic devices that would preclude MRI/fMRI/MRS imaging

• Ongoing medical condition that is deemed by the Principal Investigator to interfere with the conduct or assessments of the study

• History of infection with human immunodeficiency virus (HIV), hepatitis A, B, or C, or tuberculosis.

• History of or current chemotherapy, radiotherapy or other immunosuppressive therapy within the past 30 days. Corticosteroid treatment may be permitted at the discretion of the PI

• Abnormal laboratory values considered clinically significant per the investigator

• Failure to thrive, defined as:

  -- Falling 20 percentiles (20/100) in body weight in the 3 months preceding Screening/Baseline

• Underlying defect in immune function

• History of multiple and severe life-threatening infections

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