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    AAV gene therapy for Tay-Sachs disease

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    Authors
    Flotte, Terence R.
    Cataltepe, Oguz
    Puri, Ajit S.
    Batista, Ana Rita
    Moser, Richard P.
    McKenna-Yasek, Diane
    Douthwright, Catherine
    Gernoux, Gwladys
    Blackwood, Meghan
    Mueller, Christian
    Tai, Phillip W. L.
    Bateman, Scot T.
    Spanakis, Spiro G.
    Parzych, Julia
    Keeler, Allison M.
    Abayazeed, Aly
    Rohatgi, Saurabh
    Gibson, Laura L.
    Finberg, Robert W.
    Barton, Bruce A.
    Vardar, Zeynep
    Shazeeb, Mohammed S.
    Gounis, Matthew J.
    Brown, Robert H. Jr.
    Gray-Edwards, Heather L.
    Sena-Esteves, Miguel
    Show allShow less
    UMass Chan Affiliations
    Population and Quantitative Health Sciences
    Medicine
    Anesthesiology and Perioperative Medicine
    Neurology
    Neurosurgery
    Li Weibo Institute for Rare Diseases Research
    Horae Gene Therapy Center
    Pediatrics
    Radiology
    Document Type
    Journal Article
    Publication Date
    2022-02-10
    Keywords
    Genetic vectors
    Neurodegenerative diseases
    Congenital, Hereditary, and Neonatal Diseases and Abnormalities
    Genetics and Genomics
    Nervous System Diseases
    Neurology
    Radiology
    Therapeutics
    
    Metadata
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    Link to Full Text
    https://doi.org/10.1038/s41591-021-01664-4
    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 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.
    Source

    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

    DOI
    10.1038/s41591-021-01664-4
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/48628
    PubMed ID
    35145305
    Notes

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

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    Link to Article in PubMed

    ae974a485f413a2113503eed53cd6c53
    10.1038/s41591-021-01664-4
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