Reversibly-cloaked adenovirus with reduced immunogenicity and hepatotoxicity

University Of Washington, Seattle WA

Investigators

Abstract

This award by the Biomaterials program in the Division of Materials Research to University of Washington is to develop polymer-virus hybrid formulation that can be used to efficiently deliver nucleic acids from an intravenous injection. Adenovirus, the gene delivery vehicle that is currently most frequently used in clinical trials, is limited by its immunogenicity and hepatotoxicity. With this award, polymers will be prepared that will self-assemble on the surface of adenovirus serotype 5 and shield the virus from undesirable interactions, thereby reducing toxicity, and innate and cellular immune response to these vehicles. These polymers will include peptides that facilitate binding to the adenovirus surface that will be specifically released after cellular uptake through enzymatic degradation and a polymer backbone that provides general resistance to protein binding. Materials will be synthesized using living radical polymerization, thus yielding well-controlled materials produced by a scalable process. At the successful conclusion of this research, a single material that can be used as a polymer shield for any Ad5 delivery vector is expected. Through this work, students from high school, undergraduate, graduate and post-doctoral levels will be trained in polymer and peptide synthesis, gene delivery and immunology. In addition, this research area will be integrated into new graduate level curriculum. The researcher will also introduce this project and related drug delivery work to the local public through various outreach programs. Gene therapy is the treatment of disease using nucleic acid-based drugs. A current limitation in broad application of gene therapy is inadequate delivery systems for these types of drugs. Viral delivery vehicles that are based on deactivated, bioengineered adenovirus, are recognized by most human immune systems, resulting in both fast removal of the adenovirus and an inflammatory response in the patient. In addition, the virus causes toxicity to the liver. To address this significant need, this project will develop synthetic coatings to mask adenoviral delivery vehicles from the immune system during circulation. After uptake into cells, the synthetic coating will be shed, allowing the virus to deliver the nucleic acid drugs. This work is expected to open new avenues for gene therapy by introducing polymer-adenoviral hybrid formulations that can be administered at substantially reduced doses and with improved safety profiles. Scientists from the high school, undergraduate, graduate and post-doctoral levels will be trained through this multidisciplinary research. The research team will also introduce this project and related drug delivery work to the local public through outreach programs such as Math Academy and Engineering Open House.