INTERFERONS IMPAIR EARLY TRANSGENE EXPRESSION BY ADENOVIRUS-MEDIATED GENE-TRANSFER IN MUSCLE-CELLS

Recombinant adenovirus (AVR) promises to be an efficient vector in gen e therapy for neuromuscular diseases, but in preclinical experiments t he expression of therapeutic genes is shorter lived in immunocompetent animals than in immunocompromised hosts. Interferons (IFN), which are known to have a role both in early antiviral activity and in late cyt otoxic immunoreaction against the virus or transduced cells, may influ ence the efficiency of gene transfer. In this study we investigated th e role of IFNs in determining the efficiency of gene transfer by AVR. AVRs expressing beta-galactosidase (beta-gal) from either a cytomegalo virus (CMV) or a troponin-l promoter were used. Muscle cells were infe cted by AVR after exposure to various IFNs. The alpha IFN treatment si gnificantly reduced (up to fivefold) the CMV promoter-driven gene expr ession in muscle cells in vitro and in immature muscles in vivo, while the least effective inhibitor was beta IFN. The decrease in gene expr ession by IFNs was more pronounced with the CMV-driven transgene than troponin-I promoter-driven one and was due to a decrease in transcript level. Intrinsic IFNs that are triggered by AVR administration can de crease the efficiency of gene transfer in muscle cells. Therefore the use of muscle specific promoters in AVR and/or IFN inhibitory agents w ill likely improve the prospects of effective gene therapy by AVR.