AAV gene therapy for Tay-Sachs disease

UMMS Affiliation

Department of Pediatrics; Horae Gene Therapy Center; Li Weibo Institute for Rare Diseases Research; Department of Neurosurgery; Department of Neurology; Department of Anesthesiology and Perioperative Medicine; Department of Medicine; Department of Population and Quantitative Health Sciences

Publication Date


Document Type



Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Genetics and Genomics | Nervous System Diseases | Neurology | Radiology | Therapeutics


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 x 10(14) 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 x 10(12) vg per thalamus) and i.t. infusion (3.9 x 10(13) 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.


Genetic vectors, Neurodegenerative diseases

DOI of Published Version



Flotte TR, Cataltepe O, Puri A, Batista AR, Moser R, McKenna-Yasek D, Douthwright C, Gernoux G, Blackwood M, Mueller C, Tai PWL, Jiang X, Bateman S, Spanakis SG, Parzych J, Keeler AM, Abayazeed A, Rohatgi S, Gibson L, Finberg R, Barton BA, Vardar Z, Shazeeb MS, Gounis M, Tifft CJ, Eichler FS, Brown RH Jr, Martin DR, Gray-Edwards HL, Sena-Esteves M. AAV gene therapy for Tay-Sachs disease. Nat Med. 2022 Feb;28(2):251-259. doi: 10.1038/s41591-021-01664-4. Epub 2022 Feb 10. PMID: 35145305. Link to article on publisher's site

Journal/Book/Conference Title

Nature medicine


Full author list omitted for brevity. For the full list of authors, see article.

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