Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 38; pp. 16363 - 16368
• Main Authors: Brantly, Mark L, Chulay, Jeffrey D, Wang, Lili, Mueller, Christian, Humphries, Margaret, Spencer, L. Terry, Rouhani, Farshid, Conlon, Thomas J, Calcedo, Roberto, Betts, Michael R, Spencer, Carolyn, Byrne, Barry J, Wilson, James M, Flotte, Terence R
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 22.09.2009; National Acad Sciences
• Subjects: Adeno-associated virus; Adeno-associated virus 1; Adult; Aged; alpha 1-Antitrypsin - blood; alpha 1-Antitrypsin - genetics; alpha 1-Antitrypsin - metabolism; alpha 1-Antitrypsin Deficiency - genetics; alpha 1-Antitrypsin Deficiency - therapy; Antibodies; Antibodies, Viral - blood; Biological Sciences; Blood; Capsid; Capsid - enzymology; Capsid - immunology; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Line; Cells; Clinical trials; Dependovirus - genetics; Dependovirus - immunology; Enzyme linked immunosorbent assay; Enzymes; epididymitis; Female; Gene Expression; Gene therapy; gene transfer; Genetic Therapy - methods; Genetic vectors; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; genome; Genomics; hematology; Humans; immune response; Injection; Injections, Intramuscular; interferon-gamma; Lymphocytes; Male; Middle Aged; Neutralizing antibodies; patients; Recombinant Fusion Proteins - blood; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; serotypes; T lymphocytes; T-Lymphocytes - cytology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Time Factors; Transgenes; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0904514106

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 10¹², 2.2 x 10¹³, and 6.0 x 10¹³ 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-γ 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.