Adeno-associated Virus Vectors for Targeted and Repeat Delivery

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Adeno-associated Virus Vectors for Targeted and Repeat Delivery Project 1 "Adeno-associated Virus Vectors for Targeted and Repeat Delivery" will capitalize on AAV vector results derived from the on-going AAV Phase I DMD clinical trial. The advent of novel AAV vectors (serotype 1-11) and the solving of the capsid crystal structure, has allowed us and others to carry out rational design of AAV capsids to generate laboratory strains of gene delivery vehicles. Using such an approach, we have been successful in engineering AAV type 2 liver tropic vectors into a muscle tropic virus using only 5 amino acids derived from AAV type 1 capsid backbone. This novel chimeric reagent (AAV 2.5) has a distinct immune profile when compared to capsid backbone of parent serotypes and has high efficiency for muscle transduction. Due to the advantages of this chimeric AAV particle we recently initiated a Phase I Gene Therapy clinical trial for DMD with Dr. Xiao. Early information derived from these efforts has provided hypothesis driven approaches to better understand basic steps such as immune response to viral capsid, viral /receptor interaction, intra-cellular trafficking, and transgene expression. In the proposed studies, we hope to capitalize on these observations by deriving a collection of disease tropic vectors with novel immune profile that will allow for repeat administration. These objectives will be carried out by availability to AAV DNA capsid library technology, selection against patient neutralizing serum (including on-going AAV clinical trial), and use of large animal models carrying muscle specific disease traits (Project 3). Our objective is to better understand the molecular mechanism of efficient vector muscle transduction that will allow these and other novel delivery reagents for skeletal and heart specific muscle gene therapy. Success of these studies will facilitate the immediate goals of Project 2 and the long-term objective of initiating clinical trial for muscle disorders.