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PLoS One. 2018 Jun 6;13(6):e0198154. doi: 10.1371/journal.pone.0198154. eCollection 2018.

Sustained AAV9-mediated expression of a non-self protein in the CNS of non-human primates after immunomodulation.

Author information

NYVAX Inc., Miami, Florida, United States of America.
Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
Wadsworth Center, New York State Department of Health, Albany, New York, United States of America.
Washington National Primate Research Center, Seattle, Washington, United States of America.
Department of Microbiology, University of Washington, Seattle, Washington, United States of America.
Neural Stem Cell Institute, Rensselaer, New York, United States of America.


A critical issue in transgene delivery studies is immune reactivity to the transgene- encoded protein and its impact on sustained gene expression. Here, we test the hypothesis that immunomodulation by rapamycin can decrease immune reactivity after intrathecal AAV9 delivery of a transgene (GFP) in non-human primates, resulting in sustained GFP expression in the CNS. We show that rapamycin treatment clearly reduced the overall immunogenicity of the AAV9/GFP vector by lowering GFP- and AAV9-specific antibody responses, and decreasing T cell responses including cytokine and cytolytic effector responses. Spinal cord GFP protein expression was sustained for twelve weeks, with no toxicity. Immune correlates of robust transgene expression include negligible GFP-specific CD4 and CD8 T cell responses, absence of GFP-specific IFN-γ producing T cells, and absence of GFP-specific cytotoxic T cells, which support the hypothesis that decreased T cell reactivity results in sustained transgene expression. These data strongly support the use of modest doses of rapamycin to modulate immune responses for intrathecal gene therapies, and potentially a much wider range of viral vector-based therapeutics.

[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors have the following interests: AIR is affiliated to NYVAX Inc., AIR is not a paid employee of NYVAX Inc., which is in the early stage of a start-up. S.J.G. has received patent royalties for intellectual property (I.P.) licensed to Asklepios Biopharma, but this I.P. was not used in this study. Asklepios has licenses for other I.P. which was used in this study [Duplexed parvovirus vectors; US7465583B2]. There are no further patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

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