Budesonide enhances repeated gene transfer and expression in the lung with adenoviral vectors.
The immune response with generation of neutralizing antiviral antibodies is an obstacle to effective repeated adenoviral gene transfer. Different immunosuppressive drugs facilitate repeat administration of adenovectors, but the clinical utility is uncertain because of systemic side effects. We investigated the use of topical corticosteroid in improving gene expression after repeated injection of adenovectors into mouse lungs. Using a vector expressing murine interleukin-6 (mIL-6) as a marker cytokine for gene expression, we show that budesonide given around exposure to adenovirus to the lung significantly maintained high levels of expressed transgene protein in bronchoalveolar lavage fluid (BALF) after as many as four consecutive injections of virus at two weekly intervals (p = 0.02 versus saline). Differences between treatment groups were most obvious 4 and 6 wk after the initial exposure to adenovirus (equivalent to three and four total exposures). In Week 4, transgene mIL-6 concentration was 2,327 +/- 955 pg/ml in budesonide compared with 336 +/- 246 pg/ml in saline-treated mice (p = 0.001). However, budesonide did not significantly protect transgene expression beyond Week 8 (four prior exposures). The improved transgene expression in budesonide-treated compared with saline-treated animals was associated with a reduction, but not prevention of neutralizing antiviral antibodies (BALF p < 0.001, serum p = 0.04). We conclude that budesonide can be valuable in gene therapy of the lung where repeated transient gene transfer is necessary.
Kolb
M
M
Department of Pathology and Molecular Medicine and Centre for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada.
Inman
M
M
Margetts
P J
PJ
Galt
T
T
Gauldie
J
J
D000256:Adenoviridae / Q000276:immunology; D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000914:Antibodies, Viral / Q000032:analysis; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D019819:Budesonide / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005938:Glucocorticoids; D007074:Immunoglobulin G / Q000097:blood; D015850:Interleukin-6 / Q000032:analysis; D008171:Lung Diseases / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C
D000893:Anti-Inflammatory Agents; D000914:Antibodies, Viral; D005938:Glucocorticoids; D007074:Immunoglobulin G; D015850:Interleukin-6; D019819:Budesonide