Sandhoff Disease Ganglioside, Tay-Sachs Disease Ganglioside
Conditions
Keywords
Sandhoff, Tay-Sachs, gangliosidosis
Brief summary
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.
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.
Interventions
BIOLOGICALblood sample
collecting blood sample for various analyses
Sponsors
Assistance Publique - Hôpitaux de Paris
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
5 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | 18 months | 100% increase in neuronal β-hexosaminidase enzyme activity after cross-correction. |
Countries
France
Contacts
CONTACTYann NADJAR, MD
Outcome results
None listed