Grant: Fellowship: Bisby (Prize)

Gene therapy is an approach to identify cells that lack a particular protein and introduce genes that will express this missing protein thus correcting the deficiency and disease state. Hemophilia is an attractive disease for this approach as levels of the Factor IX protein that are lost need only be replaced to 1% of their normal circulating state in order to prevent the severe complications resulting from the impaired ability to clot blood. Several viral vectors have been isolated for this approach each with their own strengths and limitations. In particular, the adverse features of vector therapy must be addressed before they can be successfully implemented in human clinical trials including preventing integration of the vector in essential sites of the human genome and avoiding a massive immune response when the vector is administered. The strategy which is proposed is to create new vectors that are a combination of fragments of the existing vectors. A battery of tests can then be performed in established rodent and canine models to determine the function of each section of the vectors and to select the vector that meets the criteria for optimal treatment in hemophilia. Creating an AAV vector that is tailored to prevent the adverse effects while maintaining maximal delivery and expression of the target gene is an essential process with profound implications. This has the potential to improve the lives of the approximately 1 in 25,000 males who are affected with hemophilia B. The techniques that are developed here also have the added benefit of being applied to target several other diseases with a strong identified genetic component.