UMMS Affiliation

Department of Pediatrics; Gene Therapy Center; Department of Surgery

Publication Date


Document Type



Dependovirus; Gene Therapy; Genetic Vectors; Simplexvirus; Transfection; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency


Allergy and Immunology | Genetics and Genomics | Pediatrics


Recombinant 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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This is a copy of an article published in Human Gene Therapy © 2011 Mary Ann Liebert, Inc. and available online at:

DOI of Published Version



Hum Gene Ther. 2011 Oct;22(10):1239-47. Epub 2011 Aug 24. Link to article on publisher's website

Journal/Book/Conference Title

Human gene therapy

Related Resources

Link to article in PubMed

PubMed ID