Hematology 2003 559 Congenital Bleeding Disorders Margaret E. Rick, Christopher E. Walsh, and Nigel S. Key Both clinical and basic problems related to the congenital bleeding disorders continue to confront hematologists. On the forefront are efforts to bring genetic correction of the more common bleeding disorders such as hemophilia A to the clinic in a safe and accessible manner. A second issue, particularly for patients with hemophilia, is the development of inhibitors—questions of how they arise and how to prevent and treat these problems that confound otherwise very successful replace- ment therapy and allow patients to maintain normal lifestyles. A third issue is the continuing question of diagnosis and management of von Willebrand disease, the most common congenital bleeding disorder, especially in individuals who have borderline laboratory values, but have a history of clinical bleeding. In Section I, Dr. Christopher Walsh discusses general principles of effective gene transfer for the hemophilias, specific information about viral vectors and non-viral gene transfer, and alterna- tive target tissues for factor VIII and factor IX production. He highlights information about the immune response to gene transfer and reviews data from the hemophilia gene transfer trials to date. The future prospects for newer methods of therapy such as RNA repair and the use of gene- modified circulating endothelial progenitors are presented as possible alternatives to the more traditional gene therapy approaches. In Section II, Dr. Nigel Key focuses on inhibitor development in patients with hemophilia A. He reviews the progress in our understanding of the risk factors and presents newer information about the immunobiology of inhibitor development. He discusses the natural history of these inhibitors and the screening, laboratory diagnosis, and treatment, including the use of different modalities for the treatment of acute bleeding episodes. Dr. Key also presents information about the eradica- tion of inhibitors by immune tolerance induction and reviews recent information from the interna- tional registries regarding the status and success of immune tolerance induction. In Section III, Dr. Margaret Rick discusses the diagnosis, classification, and management of von Willebrand disease. Attention is given to the difficulty of diagnosis in patients with mild bleed- ing histories and borderline laboratory test results for von Willebrand factor. She presents the value of different laboratory assays for both diagnosis and classification, and she relates the classifica- tion of von Willebrand disease to the choice of treatment and to the known genetic mutations. Practical issues of diagnosis and treatment, including clinical cases, will be presented. I. GENE TRANSFER FOR THE HEMOPHILIAS Christopher E. Walsh, MD, PhD* Genetic correction of the hemophilias is a model sys- tem for developing a basic understanding of how gene therapy will be achieved. The goals for hemophilia gene transfer require the long-term therapeutic production of the coagulant protein without stimulation of an im- mune response to the transgene product or the vector. Several groups have demonstrated sustained expression of clotting factors at therapeutic levels in animal mod- els of hemophilia leading to Phase I clinical trials. To date, 5 different trials, 3 for hemophilia A and 2 for hemophilia B, have enrolled approximately 40 patients with severe hemophilia. Here we will focus on the cur- rent gene transfer strategies for treating the hemophilias. Current treatment for hemophilia-related bleeding episodes uses intravenous infusion of purified and re- combinant factor proteins, which is effective but tran- sient because of the short half-life of the proteins. This treatment is expensive, restricts the prophylactic use of factors that can lead to crippling joint disease, and may transmit infectious agents. Effective hemophilia gene transfer requires that a sustained, long-term (for years) production of coagulation factor at therapeutic levels be generated. Thus, the method of gene delivery must * Mount Sinai Medical Center, 1 Gustave Levy Place, Room 24-42C, Annenberg Building, New York NY 10029