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Newly‐developed Sendai virus vector for retinal gene transfer: reduction of innate immune response via deletion of all envelope‐related genes
Author(s) -
Murakami Yusuke,
Ikeda Yasuhiro,
Yonemitsu Yoshikazu,
Tanaka Sakura,
Kondo Haruhiko,
Okano Shinji,
Kohno Riichiro,
Miyazaki Masanori,
Inoue Makoto,
Hasegawa Mamoru,
Ishibashi Tatsuro,
Sueishi Katsuo
Publication year - 2008
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.1142
Subject(s) - biology , proinflammatory cytokine , immune system , sendai virus , transgene , innate immune system , retinal , genetic enhancement , immunology , gene , virus , inflammation , genetics , biochemistry
Background Recombinant Sendai virus vectors (rSeV) constitute a new class of cytoplasmic RNA vectors that have shown efficient gene transfer in various organs, including retinal tissue; however, the related immune responses remain to be overcome in view of clinical applications. We recently developed a novel rSeV from which all envelope‐related genes were deleted (rSeV/dFdMdHN) and, in the present study, assess host immune responses following retinal gene transfer. Methods rSeV/dFdMdHN or conventional F‐gene deleted rSeV (rSeV/dF) was injected into subretinal space of adult Wistar rats or C57BL/6 mice. The transgene expression and histopathological findings were assessed at various time points. Immunological assessments, including the expression of proinflammatory cytokines, natural killer (NK)‐cell activity, as well as SeV‐specific cytotoxic T lymphocytes (CTLs) and antibodies, were performed following vector injection. Results rSeV/dFdMdHN showed high gene transfer efficiency into the retinal pigment epithelium at an equivalent level to that seen with rSeV/dF. In the early phase, the upregulation of proinflammatory cytokines, local inflammatory cell infiltration and tissue damage that were all prominently seen in rSeV/dF injection were dramatically diminished using rSeV/dFdMdHN. NK cell activity was also decreased, indicating a reduction of the innate immune response. In the later phase, on the other hand, CTL activity and anti‐SeV antibodies were similarly induced, even using rSeV/dFdMdHN, and resulted in transient transgene expression in both vector types. Conclusions Deletion of envelope‐related genes of rSeV dramatically reduces the vector‐induced retinal damage and may extend the utility for ocular gene transfer; however, further studies regulating the acquired immune response are required to achieve long‐term transgene expression of rSeV. Copyright © 2007 John Wiley & Sons, Ltd.