First-in-Human Study of TSHA-101 Gene Therapy for Treatment of Infantile Onset GM2 Gangliosidosis

Study Overview
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Brief Summary
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GM2 gangliosidoses are a group of autosomal recessive neurodegenerative diseases characterized by a deficiency of the Hex A enzyme to catabolize GM2, thereby causing GM2 accumulation within cellular lysosomes.Hex A is composed of 2 subunits, α- and β-, coded by the HEXA and HEXB genes, respectively. The primary purpose of the current study is to assess the safety and tolerability of TSHA101 administered via IT injection.

Official Title
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Phase 1/2, Open-Label Clinical Study to Evaluate the Safety and Efficacy of Intrathecal TSHA-101 Gene Therapy for Treatment of Infantile Onset GM2 Gangliosidosis

Conditions
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Infantile GM2 Gangliosidosis (Disorder)

Intervention / Treatment
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* Biological: TSHA-101


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: male or female with age less than or equal to 15 months diagnosis of GM2 gangliosidosis with genetic and enzymatic documentation of infantile disease Key Exclusion Criteria: a second neurodevelopmental disorder independent of the HEXA or HEXB inability to tolerate sedation or intrathecal administration invasive ventilatory support concomitant illness, allergies or known hypersensitivity to the required immunosuppression regimen

Ages Eligible for Study
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Maximum Age: 15 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TSHA-101<br>Subjects who will receive one-time intrathecal TSHA-101, brain volume based sliding scale for dosage | Biological: TSHA-101<br>* AAV9 viral vector containing HEXA and HEXB genes to be administered via Intrathecal injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability: Treatment-emergent Adverse Events (TEAEs) | Incidence, severity, and relatedness of TEAEs | 1 year | 
| Safety and Tolerability: Number of participants with abnormal Laboratory assessments | Number of participants with Changes from Baseline in laboratory assessments | 1 year | 
| Safety and Tolerability: Electrocardiogram (ECG) | Changes from Baseline in 12-lead ECG findings in QT interval | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability: Viral shedding analysis | Positive presence of viral DNA from biological fluids (whole blood, urine, saliva, and stool) | 1 year | 
| Assessment of Immunogenicity: Biomarkers in serum | Summary of neutralizing antibodies (NAbs) titers for adeno-associated virus, serotype 9 (AAV9) and Hex A | 1 year | 
| Assessment of Immunogenicity: Biomarkers in serum | Summary of total antibodies (TAbs) titers for AAV9 and Hex A | 1 year | 
| Assessment of Immunogenicity: Biomarkers in peripheral blood mononuclear cells (PBMCs | Summary of PBMCs for enzyme-linked immune absorbent spot (ELISpot) assays for cytokine secretion against AAV9 and Hex A | 5 years | 
| Overall Survival | Estimated using the Kaplan-Meier method | treatment to death from any cause, up to 5 years | 
| Hex A Enzyme Activity: Cerebrospinal fluid (CSF) and serum | Change from baseline | 1 year | 
| Head Control: Number of events for abnormal head control | change from Baseline | 1 year | 
| Change from Baseline in motor function: Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) | The test consists of 16 items (body parts), where each item is tested for both sides of the body, left and right. The best score is taken for each item (with a maximum score of 4), and the scores are summed over all 16 items with a possible total CHOP-INTEND score of 64. | 1 year | 
| Change from Baseline in Motor Function: Modified Ashworth Scale | change from Baseline. Increase or decrease of muscle tone will be measured by the Modified Ashworth Scale. Frequency counts and percentages will be presented by score (0, 1, 1+, 2, 3, and 4), muscle, side, and visit for the safety population. Flexion and extension of the knee and elbow will be measured on both sides, along with hip adduction and abduction on both sides of the body. | 1 year | 
| Clinical Efficacy Assessment: Progression of Hypotonia | Assessed through neurological examinations as present or absent. Baseline to each post-Baseline visit | 1 year | 
| Clinical Efficacy Assessment: Dysphagia | Assessment of the dysphagia events- assessed as present or absent. | From onset up to 3 years, if present | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tay-Sachs disease, Sandhoff disease, GM2 gangliosidosis