Improving adenoviral vectors for muscle-directed gene therapy

Abstract

Gene therapy is a promising approach for the treatment of Duchenne Muscular Dystrophy (DMD). Adenoviral vectors (Ad) are the most commonly used vectors in gene therapy studies however, the overall large size of the Ad particles (162nm), due in part to the fiber proteins that extrude from the surface of the virion, prevent their efficient distribution in muscle. The objective of this project was to evaluate the transduction performance of Ad5 based vectors genetically modified to encode shorter fiber proteins derived from Ad serotypes 35 and 9. Optimal transduction was dependent on fiber length in some cell lines and in mdx muscle. However, fiber-modified viruses have an improved viral dispersion and improved transduction up to 10-fold in normal muscle. In addition, an optimized non-immunogenic reporter gene ideal for monitoring vector function in murine disease models was presented. The results of these experiments will contribute to the understanding of Ad transduction in muscle and aid in the design of efficient vectors for DMD therapy.