RESPIRATORY MUSCLES AS A TARGET FOR ADENOVIRUS-MEDIATED GENE-THERAPY

Authors
Citation
Bj. Petrof, RESPIRATORY MUSCLES AS A TARGET FOR ADENOVIRUS-MEDIATED GENE-THERAPY, The European respiratory journal, 11(2), 1998, pp. 492-497
Citations number
46
Categorie Soggetti
Respiratory System
ISSN journal
09031936
Volume
11
Issue
2
Year of publication
1998
Pages
492 - 497
Database
ISI
SICI code
0903-1936(1998)11:2<492:RMAATF>2.0.ZU;2-S
Abstract
The protein dystrophin is absent in the muscles of patients with Duche nne muscular dystrophy (DMD) as well as dystrophin-deficient mice with muscular dystrophy (mdx mice), The mds mouse diaphragm closely resemb les the human DMD phenotype and thus provides a useful model for studi es of dystrophin gene replacement, Recombinant adenovirus vectors (AdV s) hold promise as a means for delivering a functional dystrophin gene to muscle, As an initial step toward this goal, we have determined th e efficiency and functional consequences of AdV-mediated reporter gene transfer to the diaphragm in both normal and mds adult mice, At 1 wee k after AdV administration, there was a high level of transgene expres sion in tile diaphragm, One month later, however, elimination of trans gene expression was observed along with a significant decrease in forc e production by both normal and mds diaphragms, Immunosuppression with cyclosporine did not augment the level of transgene expression, but a beneficial effect on diaphragm force-generating capacity was observed in both groups of animals, In order to further elucidate the cellular mechanisms underlying these findings, the effects of AdV gene inactiv ation (by ultraviolet (UV) irradiation) and interference with host T-l ymphocyte subsets were examined. Both UV-inactivation of AdV and CD8T-cell deficiency were found to significantly alleviate AdV-induced re ductions in diaphragm force-generating capacity, Brief (2 day) adminis tration of a neutralizing antibody against host CD4+ T-cells also prod uced a trend towards mitigation of AdV-induced contractile dysfunction , In addition, transgene expression one month after AdV delivery nas s ignificantly enhanced with inhibition of either CD4+ or CD8+ T-cell fu nction, The data suggest two major sources of reduced force generation after recombinant adenovirus vector-mediated gene transfer to muscle: 1) a cytotoxic component associated with recombinant adenovirus vecto r transcriptional activity; and 2) an immune-based component of more d elayed onset that is primarily dependent upon CD8+ T-cell activity. Th ese results have important implications for the design of future gener ation vectors and the potential need for immunosuppressive therapy aft er recombinant adenovirus vector mediated dystrophin gene transfer to Duchenne muscular dystrophy patients.