AAV gene therapy for Tay-Sachs disease

Terence R. Flotte, Oguz Cataltepe, Ajit Puri, Ana Rita Batista, Richard Moser, Diane McKenna-Yasek, Catherine Douthwright, Gwladys Gernoux, Meghan Blackwood, Christian Mueller, Phillip W.L. Tai, Xuntian Jiang, Scot Bateman, Spiro G. Spanakis, Julia Parzych, Allison M. Keeler, Aly Abayazeed, Saurabh Rohatgi, Laura Gibson, Robert FinbergBruce A. Barton, Zeynep Vardar, Mohammed Salman Shazeeb, Matthew Gounis, Cynthia J. Tifft, Florian S. Eichler, Robert H. Brown, Douglas R. Martin, Heather L. Gray-Edwards, Miguel Sena-Esteves

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


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.

Original languageEnglish
Pages (from-to)251-259
Number of pages9
JournalNature medicine
Issue number2
StatePublished - Feb 2022


Dive into the research topics of 'AAV gene therapy for Tay-Sachs disease'. Together they form a unique fingerprint.

Cite this