UMMS Affiliation

Gene Therapy Center; Department of Pediatrics

Publication Date


Document Type



Adult; Aged; Antibodies, Viral; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Capsid; Cell Line; Dependovirus; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression; Gene Therapy; Genetic Vectors; Humans; Injections, Intramuscular; Male; Middle Aged; Recombinant Fusion Proteins; T-Lymphocytes; Time Factors; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency


Allergy and Immunology | Genetics and Genomics | Pediatrics


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.

DOI of Published Version



Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16363-8. Epub 2009 Aug 12. Link to article on publisher's site

Journal/Book/Conference Title

Proceedings of the National Academy of Sciences of the United States of America

Related Resources

Link to Article in PubMed

PubMed ID