AAV gene therapy for Tay-Sachs disease.

Abstract

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.

• Authors: 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 Finberg, Bruce A Barton, Zeynep Vardar, Mohammed Salman Shazeeb, Matthew Gounis, Cynthia J Tifft, Florian S Eichler, Robert H Brown Jr, Douglas R Martin, Heather L Gray-Edwards, Miguel Sena-Esteves
• Journal: Nature medicine (Nat Med) Vol. 28 Issue 2 Pg. 251-259 (02 2022) ISSN: 1546-170X [Electronic] United States
• PMID: 35145305 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Chemical References

• Anticonvulsants

Topics

• Anticonvulsants
• Dependovirus (genetics)
• Genetic Therapy
• Humans
• Tay-Sachs Disease (genetics, therapy)