Exploring long-term expression of therapeutic transgenes
Results from early-phase clinical trials have indicated that recombinant adeno-associated viruses (rAAV) could potentially be used for gene therapy. In each trial, however, patients have developed T cell-mediated immune responses that may interfere with therapeutic gene expression. In this episode, Terence Flotte and Christian Mueller discuss their recent study investigating T cell responses to intramuscular injection of a rAAV encoding M-type a1-antitrypsin (AAT) in patients with AAT-deficiency. Their results demonstrate that AAT expression persists for up to 12 months and suggest that immunomodulation of T cell populations may not be necessary for long-term, rAAV-mediated transgene expression.
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Citation Information: J Clin Invest. 2013;123(12):5310-5318. https://doi.org/10.1172/JCI70314.
Abstract
Recombinant adeno-associated virus (rAAV) vectors have shown promise for the treatment of several diseases; however, immune-mediated elimination of transduced cells has been suggested to limit and account for a loss of efficacy. To determine whether rAAV vector expression can persist long term, we administered rAAV vectors expressing normal, M-type α-1 antitrypsin (M-AAT) to AAT-deficient subjects at various doses by multiple i.m. injections. M-specific AAT expression was observed in all subjects in a dose-dependent manner and was sustained for more than 1 year in the absence of immune suppression. Muscle biopsies at 1 year had sustained AAT expression and a reduction of inflammatory cells compared with 3 month biopsies. Deep sequencing of the TCR Vβ region from muscle biopsies demonstrated a limited number of T cell clones that emerged at 3 months after vector administration and persisted for 1 year. In situ immunophenotyping revealed a substantial Treg population in muscle biopsy samples containing AAT-expressing myofibers. Approximately 10% of all T cells in muscle were natural Tregs, which were activated in response to AAV capsid. These results suggest that i.m. delivery of rAAV type 1–AAT (rAAV1-AAT) induces a T regulatory response that allows ongoing transgene expression and indicates that immunomodulatory treatments may not be necessary for rAAV-mediated gene therapy.
Authors
Christian Mueller, Jeffrey D. Chulay, Bruce C. Trapnell, Margaret Humphries, Brenna Carey, Robert A. Sandhaus, Noel G. McElvaney, Louis Messina, Qiushi Tang, Farshid N. Rouhani, Martha Campbell-Thompson, Ann Dongtao Fu, Anthony Yachnis, David R. Knop, Guo-jie Ye, Mark Brantly, Roberto Calcedo, Suryanarayan Somanathan, Lee P. Richman, Robert H. Vonderheide, Maigan A. Hulme, Todd M. Brusko, James M. Wilson, Terence R. Flotte
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