DOI: 10.1073/pnas.0904514106. Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy [Penn]

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

10.1073/pnas.0904514106

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

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 × 10 12 , 2.2 × 10 13 , and 6.0 × 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-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.

Bibliography

Brantly, M. L., Chulay, J. D., Wang, L., Mueller, C., Humphries, M., Spencer, L. T., Rouhani, F., Conlon, T. J., Calcedo, R., Betts, M. R., Spencer, C., Byrne, B. J., Wilson, J. M., & Flotte, T. R. (2009). Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy. Proceedings of the National Academy of Sciences, 106(38), 16363â16368.

Authors 14

Mark L. Brantly (first)
Jeffrey D. Chulay (additional)
Lili Wang (additional)
Christian Mueller (additional)
Margaret Humphries (additional)
L. Terry Spencer (additional)
Farshid Rouhani (additional)
Thomas J. Conlon (additional)
Roberto Calcedo (additional)
Michael R. Betts (additional)
Carolyn Spencer (additional)
Barry J. Byrne (additional)
James M. Wilson (additional)
Terence R. Flotte (additional)

References 31 Referenced 268

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MY Levy, LG Barron, KB Meyer, FC Szoka, Characterization of plasmid DNA transfer into mouse skeletal muscle: Evaluation of uptake mechanism, expression and secretion of gene products into blood. Gene Ther 3, 201–211 (1996). / Gene Ther / Characterization of plasmid DNA transfer into mouse skeletal muscle: Evaluation of uptake mechanism, expression and secretion of gene products into blood by Levy MY (1996)
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F Mingozzi, et al., Intramuscular administration of an AAV1 vector in humans results in capsid specific T cell responses. Mol Ther 15, 3400, (abstr). (2007). / Mol Ther by Mingozzi F (2007)
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A Poirier, et al., Toxicology and biodistribution studies of a recombinant adeno-associated virus 2-α1-antitrypsin vector. Preclinica 2, 43–51 (2004). / Preclinica / Toxicology and biodistribution studies of a recombinant adeno-associated virus 2-α1-antitrypsin vector by Poirier A (2004)
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Dates

Type	When
Created	16 years ago (Aug. 12, 2009, 10:05 p.m.)
Deposited	3 years, 3 months ago (May 23, 2022, 5:12 p.m.)
Indexed	1 month, 1 week ago (July 26, 2025, 5:05 a.m.)
Issued	15 years, 11 months ago (Sept. 22, 2009)
Published	15 years, 11 months ago (Sept. 22, 2009)
Published Online	15 years, 11 months ago (Sept. 22, 2009)
Published Print	15 years, 11 months ago (Sept. 22, 2009)

Funders 0

None

BibTeX

@article{Brantly_2009, title={Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy}, volume={106}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.0904514106}, DOI={10.1073/pnas.0904514106}, number={38}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Brantly, Mark L. and Chulay, Jeffrey D. and Wang, Lili and Mueller, Christian and Humphries, Margaret and Spencer, L. Terry and Rouhani, Farshid and Conlon, Thomas J. and Calcedo, Roberto and Betts, Michael R. and Spencer, Carolyn and Byrne, Barry J. and Wilson, James M. and Flotte, Terence R.}, year={2009}, month=sep, pages={16363–16368} }

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