AAV gene therapy for Tay-Sachs disease

Area of Science:

• Neurogenetics
• Molecular Therapy
• Rare Diseases

Background:

• Tay-Sachs disease (TSD) is a severe inherited neurological disorder caused by a deficiency in the hexosaminidase A (HexA) enzyme.
• Infantile TSD has a devastating natural history, leading to progressive neurodegeneration and early death.

Purpose of the Study:

• To evaluate the safety and proof-of-concept of adeno-associated virus (AAV) gene therapy for infantile Tay-Sachs disease.
• To assess the impact of AAV gene therapy on HexA enzyme activity and clinical outcomes in TSD patients.

Main Methods:

• An expanded-access trial involving two patients with infantile TSD (TSD-001 and TSD-002).
• Intrathecal (i.t.) administration of AAV vectors carrying HEXA and HEXB genes, with variations in dosage and delivery sites (cisterna magna, thoracolumbar junction, thalamus).
• Immunosuppression protocols were employed for both patients.

Main Results:

• Gene therapy administration was well-tolerated with no vector-related adverse events observed.
• Cerebrospinal fluid (CSF) HexA activity increased from baseline and remained stable post-treatment in both patients.
• Patient TSD-001 remained seizure-free at 5 years of age. Patient TSD-002 showed temporary stabilization but later disease progression.

Conclusions:

• AAV gene therapy demonstrates early safety and proof-of-concept in human patients with infantile TSD.
• The study provides valuable preliminary data for the development of AAV-based gene therapies for TSD.
• Further research is warranted to optimize AAV gene therapy strategies for TSD and similar neurological disorders.