TY - JOUR
T1 - AAV gene therapy for Tay-Sachs disease
AU - Flotte, Terence R.
AU - Cataltepe, Oguz
AU - Puri, Ajit
AU - Batista, Ana Rita
AU - Moser, Richard
AU - McKenna-Yasek, Diane
AU - Douthwright, Catherine
AU - Gernoux, Gwladys
AU - Blackwood, Meghan
AU - Mueller, Christian
AU - Tai, Phillip W.L.
AU - Jiang, Xuntian
AU - Bateman, Scot
AU - Spanakis, Spiro G.
AU - Parzych, Julia
AU - Keeler, Allison M.
AU - Abayazeed, Aly
AU - Rohatgi, Saurabh
AU - Gibson, Laura
AU - Finberg, Robert
AU - Barton, Bruce A.
AU - Vardar, Zeynep
AU - Shazeeb, Mohammed Salman
AU - Gounis, Matthew
AU - Tifft, Cynthia J.
AU - Eichler, Florian S.
AU - Brown, Robert H.
AU - Martin, Douglas R.
AU - Gray-Edwards, Heather L.
AU - Sena-Esteves, Miguel
N1 - Funding Information:
This work was supported in part by the BlueGenes Foundation, which had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We are also grateful for the exceptional support from the National Tay-Sachs and Allied Diseases Association and the Cure Tay-Sachs Foundation during the preclinical development of this AAV gene therapy. We thank the families that provided MRI images from their deceased children with TSD or SD to support this study. We thank A. Singh for allowing us to use the MRI images from healthy children at 7 and 12 months of age for comparison purposes. We thank A. Zimmerman and B. Wong for their assistance during this study. We also thank N. Sanil and C. Dooley in the research pharmacy for their assistance in preparing the AAV doses for administration. We acknowledge the NEALS Biorepository for providing the biofluids from patient with amyotrophic lateral sclerosis used as non-TSD control samples in this study. M. Sena-Esteves was the sponsor of the clinical trial and was responsible for production of the AAVrh8 vectors in his laboratory as described in Methods. The hexosaminidase assays and western blots were also done in his laboratory. He had no role in the clinical aspects of the trial. During the manuscript review process, R.F. passed away in August 2021.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/2
Y1 - 2022/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85124477228&partnerID=8YFLogxK
U2 - 10.1038/s41591-021-01664-4
DO - 10.1038/s41591-021-01664-4
M3 - Article
C2 - 35145305
AN - SCOPUS:85124477228
SN - 1078-8956
VL - 28
SP - 251
EP - 259
JO - Nature Medicine
JF - Nature Medicine
IS - 2
ER -