Gene Transfer as an Approach to Treating Hemophilia

ABSTRACT

Gene therapy is a novel area of therapeutics in which the active agent is a nucleic acid sequence rather than a protein or small molecule. Successful clinical applications of gene transfer have been limited to date because of shortcomings in the available gene delivery vehicles. The goal of gene transfer for hemophilia is to achieve sustained expression of factor (F) VIII or FIX at levels high enough to improve the symptoms of the disease. Hemophilia has proved to be an attractive model for those interested in gene transfer, and multiple gene transfer strategies are currently being investigated. So far, five different trials, three for hemophilia A and two for hemophilia B, have enrolled approximately 40 patients with severe hemophilia. This article summarizes the gene transfer strategies being investigated, the available preclinical data, and the early clinical results. In the past year, several groups have demonstrated sustained expression of clotting factors at levels of 5 to 10% of normal in large animal models of hemophilia. The goal of the ongoing clinical studies is to determine whether these results can safely be extended to humans.

KEYWORD

Gene therapy - adenovirus - retrovirus - AAV - hemophilia A - hemophilia B

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1 *These include the fact that, in muscle, post-translational modifications become rate limiting at high MOIs⁵⁵ and that risk of inhibitory antibody formation rises as the dose/site rises. ⁵⁶