• DOI:10.1038/s41591-021-01664-4
• Corpus ID: 246748772

AAV gene therapy for Tay-Sachs disease.

@article{Flotte2022AAVGT,
  title={AAV gene therapy for Tay-Sachs disease.},
  author={Terence R. Flotte and Oguz Cataltepe and A.S. Puri and Ana Rita Batista and Richard P. Moser and Diane M. McKenna-Yasek and Catherine L Douthwright and Gwladys Gernoux and Meghan Blackwood and Christian Mueller and Phillip W. L. Tai and Xuntian Jiang and Scot T. Bateman and Spiro G. Spanakis and Julia Parzych and Allison M. Keeler and Aly H Abayazeed and Saurabh Rohatgi and Laura L. Gibson and Robert Finberg and Bruce Barton and Zeynep Vardar and Mohammed Salman Shazeeb and Matthew J. Gounis and Cynthia J. Tifft and Florian S. Eichler and Robert H Brown and Douglas R Martin and Heather L. Gray-Edwards and Miguel Sena-Esteves},
  journal={Nature medicine},
  year={2022}
}

• T. Flotte, O. Cataltepe, +27 authors M. Sena-Esteves
• Published 10 February 2022
• Medicine, Biology
• Nature medicine

Tay-Sachs disease (TSD) is an inherited neurological disorder caused by deficiency of hexosaminidase A (HexA). Here, we describe an adeno-associated virus (AAV) gene therapy expanded-access trial in two patients with infantile TSD (IND 18225) with safety as the primary endpoint and no secondary endpoints. Patient TSD-001 was treated at 30 months with an equimolar mix of AAVrh8-HEXA and AAVrh8-HEXB administered intrathecally (i.t.), with 75% of the total dose (1 × 1014 vector genomes (vg)) in the cisterna magna and 25% at the thoracolumbar junction. Patient TSD-002 was treated at 7 months by combined bilateral thalamic (1.5 × 1012 vg per thalamus) and i.t. infusion (3.9 × 1013 vg). Both patients were immunosuppressed. Injection procedures were well tolerated, with no vector-related adverse events (AEs) to date. Cerebrospinal fluid (CSF) HexA activity increased from baseline and remained stable in both patients. TSD-002 showed disease stabilization by 3 months after injection with ongoing myelination, a temporary deviation from the natural history of infantile TSD, but disease progression was evident at 6 months after treatment. TSD-001 remains seizure-free at 5 years of age on the same anticonvulsant therapy as before therapy. TSD-002 developed anticonvulsant-responsive seizures at 2 years of age. This study provides early safety and proof-of-concept data in humans for treatment of patients with TSD by AAV gene therapy.