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    Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing α1-antitrypsin: interim results

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    Authors
    Flotte, Terence R.
    Trapnell, Bruce C.
    Humphries, Margaret
    Carey, Brenna
    Calcedo, Roberto
    Rouhani, Farshid
    Campbell-Thompson, Martha
    Yachnis, Anthony T.
    Sandhaus, Robert A.
    McElvaney, Noel G.
    Mueller, Christian
    Messina, Louis M.
    Wilson, James M.
    Brantly, Mark L.
    Knop, David R.
    Ye, Guo-jie
    Chulay, Jeffrey D.
    Show allShow less
    UMass Chan Affiliations
    Department of Surgery
    Gene Therapy Center
    Department of Pediatrics
    Document Type
    Journal Article
    Publication Date
    2011-10-01
    Keywords
    Dependovirus
    Gene Therapy
    Genetic Vectors
    Simplexvirus
    Transfection
    alpha 1-Antitrypsin
    alpha 1-Antitrypsin Deficiency
    Allergy and Immunology
    Genetics and Genomics
    Pediatrics
    
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    Show full item record
    Abstract
    Recombinant adeno-associated virus (rAAV) vectors offer promise for the gene therapy of α(1)-antitrypsin (AAT) deficiency. In our prior trial, an rAAV vector expressing human AAT (rAAV1-CB-hAAT) provided sustained, vector-derived AAT expression for >1 year. In the current phase 2 clinical trial, this same vector, produced by a herpes simplex virus complementation method, was administered to nine AAT-deficient individuals by intramuscular injection at doses of 6.0×10(11), 1.9×10(12), and 6.0×10(12) vector genomes/kg (n=3 subjects/dose). Vector-derived expression of normal (M-type) AAT in serum was dose dependent, peaked on day 30, and persisted for at least 90 days. Vector administration was well tolerated, with only mild injection site reactions and no serious adverse events. Serum creatine kinase was transiently elevated on day 30 in five of six subjects in the two higher dose groups and normalized by day 45. As expected, all subjects developed anti-AAV antibodies and interferon-γ enzyme-linked immunospot responses to AAV peptides, and no subjects developed antibodies to AAT. One subject in the mid-dose group developed T cell responses to a single AAT peptide unassociated with any clinical effects. Muscle biopsies obtained on day 90 showed strong immunostaining for AAT and moderate to marked inflammatory cell infiltrates composed primarily of CD3-reactive T lymphocytes that were primarily of the CD8(+) subtype. These results support the feasibility and safety of AAV gene therapy for AAT deficiency, and indicate that serum levels of vector-derived normal human AAT >20 μg/ml can be achieved. However, further improvements in the design or delivery of rAAV-AAT vectors will be required to achieve therapeutic target serum AAT concentrations.
    Source
    Hum Gene Ther. 2011 Oct;22(10):1239-47. Epub 2011 Aug 24. Link to article on publisher's website
    DOI
    10.1089/hum.2011.053
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/43846
    PubMed ID
    21609134
    Related Resources
    Link to article in PubMed
    Rights

    This is a copy of an article published in Human Gene Therapy © 2011 Mary Ann Liebert, Inc. and available online at: http://www.liebertonline.com.

    ae974a485f413a2113503eed53cd6c53
    10.1089/hum.2011.053
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