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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Infantile GM2 Gangliosidosis (Disorder)
• Intervention / Treatment: Biological: TSHA-101

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Kingston, Ontario, Canada, K7L 2V7
      • Queen's University/Kingston Health Sciences Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 year (Child)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Dr. Anupam Sehgal
• Collaborators: Taysha Gene Therapies, Inc.; GlycoNet
• Investigators: Principal Investigator: Anupam Sehgal, MBBS, Queen's University

Study record dates

Study Major Dates

• Study Start (Actual): March 12, 2021
• Primary Completion (Anticipated): March 12, 2027
• Study Completion (Anticipated): March 12, 2027

Study Registration Dates

• First Submitted: February 22, 2021
• First Submitted That Met QC Criteria: March 11, 2021
• First Posted (Actual): March 15, 2021

Study Record Updates

• Last Update Posted (Actual): May 9, 2023
• Last Update Submitted That Met QC Criteria: May 8, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Tay-Sachs disease; Sandhoff disease; GM2 gangliosidosis
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Lipidoses; Lipid Metabolism, Inborn Errors; Gangliosidoses; Gangliosidoses, GM2; Tay-Sachs Disease
• Other Study ID Numbers: TSHA-101-IST-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No