GM1 Gangliosidosis
Conditions
Keywords
GM1 Gangliosidosis, Lysosomal Storage Disease, Landing Disease
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.
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 for which the first stage (Stage 1) is for safety evaluation (FIH) and the second stage (Stage 2) will establish efficacy as compared to the natural history of the disease. The participants with infantile GM1 gangliosidosis will receive a single dose of LYS-GM101 by intracisternal injection. After a two-year evaluation period (main part of the study), each participant will be followed for an additional three-year long-term follow-up period.
Interventions
GENETICLYS-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
Sponsors
LYSOGENE
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 3 Years
Healthy volunteers
No
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 * Children with late infantile GM1 gangliosidosis less than 3 years of age with ability to sit
Exclusion criteria
* Uncontrolled seizure disorder. Patients who are stable on anti-convulsive medications may be included * More than 40% brain atrophy as measured by MRI total brain volume at screening * Current participation in a clinical trial of another investigational medicinal product * Past participation in a gene therapy trial * History of hematopoietic stem cell transplantation * Any condition that would contraindicate treatment with immunosuppressant therapy * Presence of concomitant medical condition or anatomical abnormality precluding lumbar puncture or intracisternal injection * Presence of any permanent items (e.g., metal braces) precluding undergoing MRI * History of non-GM1 gangliosidosis medical condition that would confound scientific rigor or interpretation of results * 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 * Any vaccination 1 month prior to the planned immunosuppressant treatment * Serology consistent with HIV exposure or consistent with active hepatitis B or C infection * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 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: Change from baseline in biochemistry laboratory parameters | Up to 6 months (multiple visits) | Change from baseline in biochemistry laboratory parameters |
| 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
Countries
France, United Kingdom, United States
Outcome results
None listed