Translational Potential of ex Vivo Gene Therapy in GM2 Gangliosidosis (GM2-TGEX)

The project aims to optimize and validate this new therapeutic strategy using cells from GM2 patients to evaluate the cross-correction of neurons in vitro by the culture medium of genetically modified myeloid cell lines. The ultimate goal is to demonstrate the potential of CHS-TGEX as an effective treatment in humans for GM2 gangliosidosis.

Study Overview

• Status: Not yet recruiting
• Conditions: Tay-Sachs Disease Ganglioside; Sandhoff Disease Ganglioside
• Intervention / Treatment: Biological: blood sample

Detailed Description

β-hexosaminidase (β-Hex) is a lysosomal enzyme essential for the degradation of GM2 ganglioside, a glycosphingolipid found mainly in the central nervous system. It is composed of α and β subunits, encoded by the HEXA and HEXB genes, respectively, which combine in different dimers. Mutations in HEXA or HEXB cause Tay-Sachs disease (TSD) and Sandhoff disease (SD), two lysosomal storage disorders that lead to the accumulation of gangliosides in the brain and progressive neurodegeneration. The infantile forms are rapidly fatal, while the late forms progress more slowly, with ataxia, motor weakness, and psychiatric disorders.

No curative treatment exists. Intracerebral gene therapy trials using AAV vectors are underway in children, but uncertainties remain regarding their long-term safety and efficacy. The investigators propose an alternative approach using ex vivo gene therapy on hematopoietic stem cells (HSC-TGEX) with lentiviral vectors integrating the human HEXA and HEXB genes. These modified cells can generate myeloid lineages capable of producing and secreting β-hexosaminidase.

The project aims to optimize and validate this new therapeutic strategy using cells from GM2 patients to evaluate the cross-correction of neurons in vitro by the culture medium of genetically modified myeloid cell lines. The ultimate goal is to demonstrate the potential of CHS-TGEX as an effective treatment in humans for GM2 gangliosidosis.

• Study Type: Observational
• Enrollment (Estimated): 6

Contacts and Locations

• Study Contact: Name: Yann NADJAR, MD; Phone Number: +33 01 42 16 17 52; Email: yann.nadjar@aphp.fr

Study Locations

• France
  • Paris, France, 75013
    • Département de Neurologie
    • Contact: Yann NADJAR, MD; Phone Number: +33 01 42 16 17 52; Email: yann.nadjar@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

patients with GM2 gangliosidosis

Description

Inclusion Criteria:

• Proven diagnosis of GM2 gangliosidosis (decreased β-hexosaminidase enzyme activity and/or biallelic pathogenic variants in the HEXA or HEXB gene)
• Age ≥ 5 years
• Blood sample planned as part of treatment

Exclusion Criteria:

• Opposition from the patient or legal guardians
• Contraindication to venous sampling
• Patient under guardianship or curatorship
• Patient not covered by social security
• Patient covered by AME (State Medical Aid)
• Weight < 25 kg for minor patients

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
GM2 gangliosidosis; patients with GM2 gangliosidosis	Biological: blood sample; collecting blood sample for various analyses

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Demonstrate effective cross-correction between myeloid cell lines (derived from patients) that have undergone ex vivo gene therapy and in vitro neurons derived from iPSCs from patients with GM2 gangliosidosis.	100% increase in neuronal β-hexosaminidase enzyme activity after cross-correction.	18 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): May 1, 2026
• Study Completion (Estimated): November 1, 2027

Study Registration Dates

• First Submitted: February 25, 2026
• First Submitted That Met QC Criteria: February 25, 2026
• First Posted (Actual): March 3, 2026

Study Record Updates

• Last Update Posted (Actual): March 6, 2026
• Last Update Submitted That Met QC Criteria: March 4, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Tay-Sachs; Sandhoff; gangliosidosis
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Lipid Metabolism Disorders; Lysosomal Storage Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases, Nervous System; Sphingolipidoses; Lipidoses; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Gangliosidoses; Investigative Techniques; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Blood Specimen Collection
• Other Study ID Numbers: APHP260012

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