Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing α1-antitrypsin: interim results.
AuthorsFlotte, Terence R
Trapnell, Bruce C
Yachnis, Anthony T
Sandhaus, Robert A
McElvaney, Noel G
Messina, Louis M
Wilson, James M
Knop, David R
Chulay, Jeffrey D
AffiliationUniversity of Massachusetts Medical School, 55 Lake Avenue North,Worcester, MA 01655, USA. Terry.Flotte@umassmed.edu
Dose-Response Relationship, Drug
Enzyme-Linked Immunospot Assay
alpha 1-Antitrypsin Deficiency
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CitationPhase 2 clinical trial of a recombinant adeno-associated viral vector expressing α1-antitrypsin: interim results. 2011, 22 (10):1239-47 Hum. Gene Ther.
JournalHuman gene therapy
AbstractRecombinant 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.
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- Authors: Brantly ML, Chulay JD, Wang L, Mueller C, Humphries M, Spencer LT, Rouhani F, Conlon TJ, Calcedo R, Betts MR, Spencer C, Byrne BJ, Wilson JM, Flotte TR
- Issue date: 2009 Sep 22
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- Authors: Chulay JD, Ye GJ, Thomas DL, Knop DR, Benson JM, Hutt JA, Wang G, Humphries M, Flotte TR
- Issue date: 2011 Feb
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- Phase I trial of intramuscular injection of a recombinant adeno-associated virus alpha 1-antitrypsin (rAAV2-CB-hAAT) gene vector to AAT-deficient adults.
- Authors: Flotte TR, Brantly ML, Spencer LT, Byrne BJ, Spencer CT, Baker DJ, Humphries M
- Issue date: 2004 Jan
- Human Treg responses allow sustained recombinant adeno-associated virus-mediated transgene expression.
- Authors: Mueller C, Chulay JD, Trapnell BC, Humphries M, Carey B, Sandhaus RA, McElvaney NG, Messina L, Tang Q, Rouhani FN, Campbell-Thompson M, Fu AD, Yachnis A, Knop DR, Ye GJ, Brantly M, Calcedo R, Somanathan S, Richman LP, Vonderheide RH, Hulme MA, Brusko TM, Wilson JM, Flotte TR
- Issue date: 2013 Dec