A Safety and Efficacy Study of LYS-GM101 Gene Therapy in Patients With GM1 Gangliosidosis
Study Details
Study Description
Brief Summary
LYS-GM101 is a gene therapy for GM1 gangliosidosis intended to deliver a functional copy of the GLB1 gene to the central nervous system. This study will assess, in a 2-stage adaptive-design, the safety and efficacy of treatment in subjects with infantile GM1 gangliosidosis.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Detailed Description
GM1 gangliosidosis is a fatal autosomal recessive disease caused by mutations in the GLB1 gene leading to accumulation of GM1 ganglioside in neurons and progressive neurodegeneration. There are three pediatric subtypes: early infantile, late infantile and juvenile. This is an interventional, multicenter, single-arm, 2-stage adaptive design study of LYS-GM101. In the first safety and proof-of-concept stage of the study, 4 subjects with infantile GM1 gangliosidosis will receive a single dose of LYS-GM101 by intracisternal injection. The second stage of the study is confirmatory and will include additional patients with GM1 gangliosidosis.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: 8x10^12 vg/Kg LYS-GM101 Subjects will receive a single infusion: 8x10^12 vg/Kg LYS-GM101 |
Genetic: LYS-GM101
LYS-GM101 is an adeno-associated viral vector serotype rh.10 (AAVrh.10) carrying the human β-galactosidase gene, formulated as a suspension for injection
|
Outcome Measures
Primary Outcome Measures
- Stage 1: Physical examination by body system [Up to 6 months (multiple visits)]
Physical examination by body system: normal/abnormal and change from previous assessment
- Stage 1: Neurological examination [Up to 6 months (multiple visits)]
Neurological examination: normal/abnormal motor activity and coordination, and change from previous assessment
- Stage 1: Vital signs: change from baseline in heart rate [Up to 6 months (multiple visits)]
Vital signs: change from baseline in heart rate
- Stage 1: Vital signs: change from baseline in body temperature [Up to 6 months (multiple visits)]
Vital signs: change from baseline in body temperature
- Stage 1: Vital signs: change from baseline in diastolic and systolic blood pressure [Up to 6 months (multiple visits)]
Vital signs: change from baseline in diastolic and systolic blood pressure
- Stage 1: Imaging: presence of bleeding post-administration [Up to 6 months (multiple visits)]
Imaging: presence of bleeding post-administration
- Stage 1: Change from baseline in biochemistry laboratory parameters [Up to 6 months (multiple visits)]
Change from baseline in biochemistry laboratory parameters
- Stage 1: Change from baseline in coagulation and hematology laboratory parameters [Up to 6 months (multiple visits)]
Change from baseline in coagulation and hematology laboratory parameters
- Stage 1: Incidence of treatment-emergent adverse event and serious adverse events [Up to 6 months (multiple visits)]
Incidence of treatment-emergent adverse event and serious adverse events
- Stage 1: Assessment of humoral immune response by measurement of antibodies anti-AAV and anti-beta-galactosidase (ELISA) and cellular immune response by beta-galactosidase-specific T-cell proliferation assay [Up to 6 months (multiple visits)]
Assessment of humoral immune response by measurement of antibodies anti-AAV and anti-beta-galactosidase (ELISA) and cellular immune response by beta-galactosidase-specific T-cell proliferation assay
Secondary Outcome Measures
- Motor Function [Up to 2 years (multiple visits)]
Assess change from baseline in motor function using the Hammersmith Infant Neurological Evaluation (HINE) or Hammersmith Functional Motor Scale-Expanded (HFMSE) instruments
- Brain MRI [Up to 2 years (multiple visits)]
Assess brain atrophy and brain volume
- Developmental changes (VABS-II) [Up to 2 years (multiple visits)]
Assess developmental change from baseline in the Vineland Adaptive Behavior Scale-II-Expanded Interview (VABS-II) instrument
- Developmental changes (BSID-III or KABC-II) [Up to 2 years (multiple visits)]
Assess developmental change from baseline in the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III) or the Kaufman Assessment Battery for Children, 2nd Edition (KABC-II) instruments
- Blood and cerebrospinal fluid (CSF) biomarkers (beta-galactosidase) [Up to 2 years (multiple visits)]
Assess change in beta-galactosidase activity measured from baseline
- Blood and cerebrospinal fluid (CSF) biomarkers (GM1 ganglioside) [Up to 2 years (multiple visits)]
Assess change in GM1 ganglioside level measured from baseline
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Documented GM1 gangliosidosis diagnosis based on genotyping confirming the β-gal gene mutations and/or documented deficiency of β-gal enzyme by laboratory testing
-
Children with early infantile GM1 gangliosidosis less than 12 months of age with ability to swallow
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Children with late infantile GM1 gangliosidosis less than 3 years of age with ability to sit
Exclusion Criteria:
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Uncontrolled seizure disorder. Patients who are stable on anti-convulsive medications may be included
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More than 40% brain atrophy as measured by MRI total brain volume at screening
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Current participation in a clinical trial of another investigational medicinal product
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Past participation in a gene therapy trial
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History of hematopoietic stem cell transplantation
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Any condition that would contraindicate treatment with immunosuppressant therapy
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Presence of concomitant medical condition or anatomical abnormality precluding lumbar puncture or intracisternal injection
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Presence of any permanent items (e.g., metal braces) precluding undergoing MRI
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History of non-GM1 gangliosidosis medical condition that would confound scientific rigor or interpretation of results
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Rare and unrelated serious comorbidities, e.g., Down syndrome, intraventricular hemorrhage in the new-born period, extreme low birth weight (<1500 grams) or known bleeding disorders
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Any vaccination 1 month prior to the planned immunosuppressant treatment
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Serology consistent with HIV exposure or consistent with active hepatitis B or C infection
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Grade 2 or higher lab abnormalities for Liver function tests (LFT), bilirubin, creatinine, hemoglobin, white blood cell (WBC) count, platelet count, prothrombin time (PT), and partial thromboplastin time (PTT), according to CTCAE v5.0
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Children's Hospital of Orange County (CHOC) | Orange | California | United States | 92868 |
| 2 | Hôpital Armand-Trousseau, Centre de Référence des Maladies Lysosomales (CRML), Service de Neuropédiatrie | Paris | France | 75012 | |
| 3 | Manchester University NHS Foundation Trust | Manchester | United Kingdom | M13 9WL |
Sponsors and Collaborators
- LYSOGENE
Investigators
- Study Director: Clinical Operations, LYSOGENE
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- P1-GM-101