UMass Chan Medical School Faculty Publications


Human Treg responses allow sustained recombinant adeno-associated virus-mediated transgene expression

UMMS Affiliation

Gene Therapy Center; Department of Pediatrics; Department of Surgery

Publication Date


Document Type



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.


UMCCTS funding

DOI of Published Version



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. Human Treg responses allow sustained recombinant adeno-associated virus-mediated transgene expression. J Clin Invest. 2013 Dec 2;123(12):5310-8. doi: 10.1172/JCI70314. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

The Journal of clinical investigation

PubMed ID