Human Treg responses allow sustained recombinant adeno-associated virus-mediated transgene expression
Gene Therapy Center; Department of Pediatrics; Department of Surgery
Medical Subject Headings
Biopsy; Capsid; Clone Cells; Dependovirus; Gene Expression Regulation; Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; *Genetic Therapy; Genetic Vectors; Humans; Injections, Intramuscular; Lymphocyte Activation; Muscle, Skeletal; Receptors, Antigen, T-Cell, alpha-beta; Recombinant Fusion Proteins; T-Lymphocytes, Regulatory; Transgenes; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency
Allergy and Immunology | Genetics | Immunoprophylaxis and Therapy | Molecular Genetics | Therapeutics
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 alpha-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 Vbeta 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.
Mueller, Christian; Chulay, Jeffrey D.; Trapnell, Bruce C.; Humphries, Margaret; Carey, Brenna; Sandhaus, Robert A.; McElvaney, Noel G.; Messina, Louis M.; Tang, Qiushi; Rouhani, Farshid N.; Campbell-Thompson, Martha; Fu, Ann Dongtao; Yachnis, Anthony; Knop, David R.; Ye, Guo-Jie; Brantly, Mark; Calcedo, Roberto; Somanathan, Suryanarayan; Richman, Lee P.; Vonderheide, Robert H.; Hulme, Maigan A.; Brusko, Todd M.; Wilson, James M.; and Flotte, Terence R., "Human Treg responses allow sustained recombinant adeno-associated virus-mediated transgene expression" (2013). University of Massachusetts Medical School Faculty Publications. 338.