Intravenous Gene Transfer With an AAV9 Vector Expressing Human <=-Galactosidase in Type II GM1 Gangliosidosis
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|ClinicalTrials.gov Identifier: NCT03952637|
Recruitment Status : Recruiting
First Posted : May 16, 2019
Last Update Posted : February 12, 2020
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.
To test if a gene therapy helps type II GM1 gangliosidosis symptoms.
People ages 2 12 with type II GM1 gangliosidosis
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
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
Central line placement
Skin biopsy: A small piece of the participant s skin will be removed.
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 will 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.
|Condition or disease||Intervention/treatment||Phase|
|Lysosomal Diseases Gangliosidosis GM1||Biological: AAV9-GLB1||Phase 1 Phase 2|
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 II GM1 gangliosidosis. Subjects in this study will be male and female, greater than or equal to 2 years old and less than or equal to 12 years old, with genetically confirmed mutations and phenotype consistent with diagnosis of Type II GM1 gangliosidosis and be seronegative for anti-AAV9 antibodies. Other inclusion/exclusion criteria apply. Each subject will receive 1.5 x 10^13 vg/kg of the gene transfer agent. A total of 4 subjects will be treated at the NIH Clinical Center in Bethesda, MD.
The primary objective of this first-in-human study is to assess the safety of the AAV9-GLB1 vector following intravenous infusion. Secondary objectives include: 1) Assess developmental change in the Growth Scale Scores on the Vineland Adaptive Behavior Scales Third Edition (Vineland-3) instrument between pre- and post-treatment, 2) Assess brain volume using a 3T MRI, and central nervous system (CNS) metabolite levels by magnetic resonance spectroscopy (MRI) between pre- and post-treatment and compared to historical controls, 3) Assess motor function using mobility scales developed as part of the natural history study, 4) Assess change in disease severity using the Clinical Global Impressions (CGI) scale.
Exploratory objectives include: 1) Plasma, cerebrospinal fluid (CSF) and urinary biomarkers of disease progression 2) Examine differences in resting state functional connectivity (RSFC) using functional MRI (fMRI), 3) Assess neurological symptoms based on clinical and developmental rating scale scores and a structured videotaped neurologic exam pre- and post-treatment, 4) Assess immune tolerance to the gene transfer vector with antibody titers to AAV9 in serum and CSF, 5) Measure GM1-galactosidase enzyme activity in CSF pre- and post-treatment, and 6) Measure GM1 ganglioside levels in CSF pre- and post-treatment.
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 II subjects. This 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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||12 participants|
|Intervention Model:||Sequential Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase 1/2 Study of Intravenous Gene Transfer With an AAV9 Vector Expressing Human Beta-galactosidase in Type II GM1 Gangliosidosis|
|Actual Study Start Date :||August 19, 2019|
|Estimated Primary Completion Date :||April 30, 2023|
|Estimated Study Completion Date :||April 30, 2023|
Single arm study only
The risks of administering this treatment in a subject with GMl gangliosidosis are not completely known. The major risk associated with intravenous infusion is from the subject's immunological response to the viral capsid and/or the beta-gal protein. To reduce this possibility, immune modulation therapy is being started prior to vector delivery and maintained for six months afterward. There is a theoretical risk that the integration of a small percentage of the rAAV vector DNA into the host cell genome could cause cellular transformation to cancer cells and lead to a malignancy. This has never been seen in subjects receiving intravenous AAV9 gene therapy so the risk of this complication, is likely very low.
- Safety [ Time Frame: Several timepoints over 3 years ]Assess the safety of the AAV9/GLB1 vector (AAV9-GLB1) following intravenous delivery.
- Developmental changes [ Time Frame: Baseline, 6 mos, year 1, 18 months, year 2, year 3 ]1. Assess developmental change in the Growth Scale Scores on the Vineland Adaptive Behavior Scales Third Edition (Vineland-3) instrument between pre- and post-treatment.
- Brain MRI/MRS/fMRI [ Time Frame: Baseline, year 1, year 2, year 3 ]2. Assess brain volume using a 3T MRI, and central nervous system (CNS) metabolite levels by magnetic resonance spectroscopy (MRI) between pre- and post- treatment and compared to historical controls
- Motor Function [ Time Frame: Baseline, 6 mos, year 1, 18 months, year 2, year 3 ]3. Assess motor function using mobility scales developed as part of the natural history study.
- CGI Scale [ Time Frame: Several timepoints over 3 years ]4. Assess change in disease severity using the Clinical Global Impressions (CGI) scale.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03952637
|Contact: Jean M Johnston||(301) firstname.lastname@example.org|
|United States, Maryland|
|National Institutes of Health Clinical Center||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 ext TTY8664111010 email@example.com|
|Principal Investigator:||Cynthia J Tifft, M.D.||National Human Genome Research Institute (NHGRI)|