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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 : October 7, 2019
Sponsor:
Collaborator:
Axovant Sciences, Inc.
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Human Genome Research Institute (NHGRI) )

Brief Summary:

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 II GM1 gangliosidosis symptoms.

Eligibility:

People ages 2 12 with type II GM1 gangliosidosis

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 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

Detailed Description:

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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


Arm Intervention/treatment
Experimental: 1
Single arm study only
Biological: AAV9-GLB1
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.




Primary Outcome Measures :
  1. Safety [ Time Frame: Several timepoints over 3 years ]
    Assess the safety of the AAV9/GLB1 vector (AAV9-GLB1) following intravenous delivery.


Secondary Outcome Measures :
  1. 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.

  2. 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 MR spectroscopy between pre- and post- treatment and compared to historical controls

  3. 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.

  4. CGI Scale [ Time Frame: Several timepoints over 3 years ]
    4. Assess change in disease severity using the Clinical Global Impressions (CGI) scale.



Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 12 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Vineland-3 Adaptive Behavior composite standard score greater than or equal to 40
  • Male or female subjects greater than or equal to 2 years old and less than or equal to 12 years old at time of enrollment
  • 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 seronegative (antibody titers < 200U/mL)
  • Agree to reside within 50 miles of the study site for at least 2 months following treatment (may include housing on NIH campus)

EXCLUSION CRITERIA:

  • Anti-AAV9 antibody titers >200U/mL
  • 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, 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:

    • Platelet count < 100,000 x 103 /mcL [Normal: males 2-13y=161- 403; females 2-13y=173-394]
    • Persistent leukopenia or leukocytosis [Total white blood cell count < 3,000 and > 12,000 x 103 /mcL respectively] [Normal: males 2-13y=4.23-13.38; females 2-13y=3.98-13.18]
    • Anemia [Hb <10 g/dL] [Normal: males 2-13y 10.2-17.5; females 10.2-15.7]
    • Prothrombin (PT) or partial thromboplastin time (PTT) >2X normal [Normal 11.6-15.2 seconds (PT); 25.3-37.3 seconds (PTT)]
    • Gamma glutamyl transferase > 2 X the baseline value [Normal: males 2-13y 3-22 U/L; females 2-13y 4-24 U/L]
    • Amylase >1.5 X ULN or > 2 X the baseline value [Normal < 91 U/L]
  • 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

Information from the National Library of Medicine

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


Contacts
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Contact: Jean M Johnston (301) 443-8628 johnstonjm@mail.nih.gov

Locations
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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    prpl@cc.nih.gov   
Sponsors and Collaborators
National Human Genome Research Institute (NHGRI)
Axovant Sciences, Inc.
Investigators
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Principal Investigator: Cynthia J Tifft, M.D. National Human Genome Research Institute (NHGRI)

Additional Information:
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Responsible Party: National Human Genome Research Institute (NHGRI)
ClinicalTrials.gov Identifier: NCT03952637     History of Changes
Other Study ID Numbers: 190101
19-HG-0101
First Posted: May 16, 2019    Key Record Dates
Last Update Posted: October 7, 2019
Last Verified: August 19, 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Human Genome Research Institute (NHGRI) ):
Lysosomal Diseases
Additional relevant MeSH terms:
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Gangliosidosis, GM1
Gangliosidoses
Sphingolipidoses
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lipidoses
Lipid Metabolism, Inborn Errors
Lysosomal Storage Diseases
Metabolic Diseases
Lipid Metabolism Disorders