Abstract Recombinant adenovirus (AVR) promises to be an efficient vector in gene therapy for neuromuscular dis- eases, but in preclinical experiments the expression of therapeutic genes is shorter lived in immunocompetent an- imals than in immunocompromised hosts. Interferons (IFN), which are known to have a role both in early antivi- ral activity and in late cytotoxic immunoreaction against the virus or transduced cells, may influence the efficiency of gene transfer. In this study we investigated the role of IFNs in determining the efficiency of gene transfer by AVR. AVRs expressing β-galactosidase (β-gal) from either a cytomegalovirus (CMV) or a troponin-I promoter were used. Muscle cells were infected by AVR after exposure to various IFNs. The αIFN treatment significantly reduced (up to fivefold) the CMV promoter-driven gene expression in muscle cells in vitro and in immature muscles in vivo, while the least effective inhibitor was βIFN. The decrease in gene expression 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 will likely improve the pros- pects of effective gene therapy by AVR. Key words Gene therapy · Adenovirus · Muscle · Interferons Abbreviations AVR Recombinant adenovirus · CMV Cytomegalovirus · β-gal E. coli β-Galactosidase · IFN Interferon · TnI Troponin-I G. Acsadi ( ✉ ) · D. O’Hagan · H. Lochmüller · S. Prescott · N. Larochelle · J. Nalbantoglu · A. Jani · G. Karpati Department of Pediatrics, and Center for Molecular Medicine, Wayne State University, Detroit, and Division of Neurology, Children’s Hospital of Michigan, 3901 Beaubien Blvd., Detroit, MI 48201-2196, USA D. O’Hagan Center for Molecular Medicine, Wayne State University, Detroit, MI 48201, USA H. Lochmüller 1 · S. Prescott · N. Larochelle · J. Nalbantoglu · G. Karpati Montreal Neurological Institute, McGill University, Montreal, PQ H3 A 2B4, Canada A. Jani Department Neurology, Wayne State University, Detroit, MI 48201, USA 1 Present address: Genzentrum, Universität München, Feodor-Lynen-Strasse 25, D-81377 Munich, Germany J Mol Med (1998) 76:442–450 © Springer-Verlag 1998 ORIGINAL ARTICLE Gyula Acsadi · David O’Hagan · Hanns Lochmüller Stephen Prescott · Nancy Larochelle Josephine Nalbantoglu · Agnes Jani · George Karpati Interferons impair early transgene expression by adenovirus-mediated gene transfer in muscle cells Received: 24 October 1997 / Accepted: 10 February 1998 Introduction Replication-deficient first generation (E1/E3 deleted) ade- noviral recombinants (AVR) are extensively used vectors in preclinical gene therapy experiments since they show high efficiency in transferring genes into several cell types, GYULA ACSADI graduated from the University Medical School of Pécs, Hungary, where he was trained in neurophysiology. He subse- quently undertook work in mo- lecular genetics at the University of Wisconsin, Madison. He is currently Clinical Instructor of Neurology, Children’s Hospital of Michigan, and Associate Fac- ulty Member at the Center for Molecular Medicine at Wayne State University, Detroit. His re- search pertains to gene therapy in neuromuscular disorders. GEORGE KARPATI obtained his M.D. degree from Dalhousie University, Halifax, Nova Scotia. He received his research training in experimen- tal immunocytochemistry at the National Institutes of Health, Bethesda, and presently holds the Isaac Walton Killam Chair of Neurology at the Montreal Neurological Institute of McGill University. His current investigative interest is gene therapy research focusing on muscle diseases and on malig- nant brain tumors.