Premium
Immune responses to transgenes encoded within gutless adenovirus vectors (HC‐Ads) delivered into the brain
Author(s) -
Xiong Weidong,
Candolfi Marianela,
Kroeger Kurt,
Puntel Mariana,
Larocque Daniel,
Liu Chunyan,
Palmer Donna,
Ng Philip,
Lowenstein Pedro R.,
Castro Maria G.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.676.2
Subject(s) - transgene , immune system , biology , genetic enhancement , genetically modified mouse , microglia , striatum , microbiology and biotechnology , inflammation , transcription (linguistics) , viral vector , gene , gene expression , immunology , neuroscience , genetics , recombinant dna , dopamine , linguistics , philosophy
Immune responses against vectors or transgenes, could reduce therapeutic transgene expression, hampering gene therapy. We demonstrated that tetracycline‐regulated HC‐Ads sustain regulated transgene expression in the brain even in the presence of systemic immune responses against Ads. Here, we assessed whether systemic immune responses against the transgene, i.e. β‐Galactosidase or the tetracycline‐dependent (TetON) regulatory transcription factors (rtTA2 S M2 and the tTS Kid ), could affect the levels of transgene expression and the safety of HC‐Ad vectors delivered into the brain. We pre‐immunized mice with plasmids encoding the TetON switch or β‐galactosidase. HC‐Ads expressing β‐Galactosidase under the control of the TetON switch were then injected into the striatum. We assessed levels and distribution of β‐Galactosidase expression, local inflammation and neuropathology. We found that systemic immunity against β‐Galactosidase, but not against the TetON switch, led to inflammatory responses in the striatum, and to a reduction of transgene expression. Thus, the regulatory TetON switch appears safe and capable of sustaining transgene expression in the brain even in the presence of an immune response against its components. S upport: NIH/NINDS 1R01 NS44556.01; 1R21‐NSO54143.01; 1UO1 NS052465.01 to M.G.C.; 1 RO1 NS 054193.01; RO1 NS 42893.01; U54 NS045309 ‐01 to P.R.L.