Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy
Mark L Brantly, Jeffrey D Chulay, Lili Wang, Christian Mueller, Margaret Humphries, L Terry Spencer, Farshid Rouhani, Thomas J Conlon, Roberto Calcedo, Michael R Betts, Carolyn Spencer, Barry J Byrne, James M Wilson, Terence R Flotte, Mark L Brantly, Jeffrey D Chulay, Lili Wang, Christian Mueller, Margaret Humphries, L Terry Spencer, Farshid Rouhani, Thomas J Conlon, Roberto Calcedo, Michael R Betts, Carolyn Spencer, Barry J Byrne, James M Wilson, Terence R Flotte
Abstract
Alpha-1 antitrypsin (AAT) deficiency is well-suited as a target for human gene transfer. We performed a phase 1, open-label, dose-escalation clinical trial of a recombinant adeno-associated virus (rAAV) vector expressing normal (M) AAT packaged into serotype 1 AAV capsids delivered by i.m. injection. Nine AAT-deficient subjects were enrolled sequentially in cohorts of 3 each at doses of 6.9 x 10(12), 2.2 x 10(13), and 6.0 x 10(13) vector genome particles per patient. Four subjects receiving AAT protein augmentation discontinued therapy 28 or 56 days before vector administration. Vector administration was well tolerated, with only mild local reactions and 1 unrelated serious adverse event (bacterial epididymitis). There were no changes in hematology or clinical chemistry parameters. M-specific AAT was expressed above background in all subjects in cohorts 2 and 3 and was sustained at levels 0.1% of normal for at least 1 year in the highest dosage level cohort, despite development of neutralizing antibody and IFN-gamma enzyme-linked immunospot responses to AAV1 capsid at day 14 in all subjects. These findings suggest that immune responses to AAV capsid that develop after i.m. injection of a serotype 1 rAAV vector expressing AAT do not completely eliminate transduced cells in this context.
Conflict of interest statement
Conflict of interest statement: T.R.F. and B.J.B. hold patents related to this research, and any monies received have been donated to the Department of Pediatrics, College of Medicine at the University of Florida. T.R.F. and B.J.B. were also founders of Applied Genetic Technologies Corporation (AGTC), the study sponsor. They do not currently hold a position with the company, and any proceeds from this study are donated to the University of Florida. T.R.F.'s laboratory receives research funding from the Alpha 1 Foundation. M.L.B. receives research funding from, holds an endowed professorship from, and is a consultant for the Alpha 1 Foundation. The University of Florida owns an interest in the study agent and also owns stock in the sponsor of the study, AGTC. The Alpha 1 Foundation is closely affiliated with AlphaNet, which owns an interest in the study agent. J.M.W. is an inventor on patents including those involving AAV1 that have been licensed to various biopharmaceutical companies.
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Source: PubMed