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

Research output: Contribution to journalArticle

Abstract

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
Volume13
Issue number6
DOIs
StatePublished - Jun 1 2018
Externally publishedYes

Fingerprint

immunomodulation
T-cells
Immunomodulation
Transgenes
Primates
transgenes
T-lymphocytes
T-Lymphocytes
Sirolimus
Proteins
proteins
immune response
Gene therapy
gene therapy
Gene expression
spinal cord
Genetic Therapy
Antibody Formation
Toxicity
Spinal Cord

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Ramsingh, A. I., Gray, S. J., Reilly, A., Koday, M., Bratt, D., Koday, M. T., ... Fuller, D. H. (2018). Sustained AAV9-mediated expression of a non-self protein in the CNS of non-human primates after immunomodulation. PLoS One, 13(6), [e0198154]. https://doi.org/10.1371/journal.pone.0198154

Sustained AAV9-mediated expression of a non-self protein in the CNS of non-human primates after immunomodulation. / Ramsingh, Arlene I.; Gray, Steven J.; Reilly, Andrew; Koday, Michael; Bratt, Debbie; Koday, Merika Treants; Murnane, Robert; Smedley, Jeremy; Hu, Yuhui; Messer, Anne; Fuller, Deborah Heydenburg.

In: PLoS One, Vol. 13, No. 6, e0198154, 01.06.2018.

Research output: Contribution to journalArticle

Ramsingh, AI, Gray, SJ, Reilly, A, Koday, M, Bratt, D, Koday, MT, Murnane, R, Smedley, J, Hu, Y, Messer, A & Fuller, DH 2018, 'Sustained AAV9-mediated expression of a non-self protein in the CNS of non-human primates after immunomodulation', PLoS One, vol. 13, no. 6, e0198154. https://doi.org/10.1371/journal.pone.0198154
Ramsingh, Arlene I. ; Gray, Steven J. ; Reilly, Andrew ; Koday, Michael ; Bratt, Debbie ; Koday, Merika Treants ; Murnane, Robert ; Smedley, Jeremy ; Hu, Yuhui ; Messer, Anne ; Fuller, Deborah Heydenburg. / Sustained AAV9-mediated expression of a non-self protein in the CNS of non-human primates after immunomodulation. In: PLoS One. 2018 ; Vol. 13, No. 6.
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