Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing α1-antitrypsin: interim results
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.
Document Type
Journal ArticlePublication Date
2011-10-01Keywords
DependovirusGene Therapy
Genetic Vectors
Simplexvirus
Transfection
alpha 1-Antitrypsin
alpha 1-Antitrypsin Deficiency
Allergy and Immunology
Genetics and Genomics
Pediatrics
Metadata
Show full item recordAbstract
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 websiteDOI
10.1089/hum.2011.053Permanent Link to this Item
http://hdl.handle.net/20.500.14038/43846PubMed ID
21609134Related Resources
Link to article in PubMedRights
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