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

Arlene I. Ramsingh, Steven J. Gray, Andrew Reilly, Michael Koday, Debbie Bratt, Merika Treants Koday, Robert Murnane, Jeremy Smedley, Yuhui Hu, Anne Messer, Deborah Heydenburg Fuller

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15 Scopus citations


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.

Original languageEnglish (US)
Article numbere0198154
JournalPloS one
Issue number6
StatePublished - Jun 2018
Externally publishedYes

ASJC Scopus subject areas

  • General


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