Sustained AAV9-mediated expression of a non-self protein in the CNS of non-human primates after immunomodulation
| Autor: | Robert D. Murnane, Yuhui Hu, Deborah H. Fuller, Michael Koday, Andrew A. Reilly, Jeremy Smedley, Merika Treants Koday, Steven J. Gray, Anne Messer, Debbie Bratt, Arlene I. Ramsingh |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Multidisciplinary Transgene Immunogenicity medicine.medical_treatment T cell lcsh:R fungi lcsh:Medicine Biology 3. Good health Cell biology Green fluorescent protein Viral vector 03 medical and health sciences 030104 developmental biology Cytokine medicine.anatomical_structure Immune system medicine Cytotoxic T cell lcsh:Q lcsh:Science |
| Zdroj: | PLoS ONE, Vol 13, Iss 6, p e0198154 (2018) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0198154 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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