A Safety and Efficacy Study of LYS-GM101 Gene Therapy in Patients With GM1 Gangliosidosis

An Open-Label Adaptive-Design Study of Intracisternal Adenoassociated Viral Vector Serotype rh.10 Carrying the Human β-Galactosidase cDNA for Treatment of GM1 Gangliosidosis

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.

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.

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