Gene therapy for hereditary hematological disorders.

The year 2000 saw the first successful treatment of a genetic disorder by gene therapy. Pediatric patients with X-linked severe combined immunodeficiency disorder (SCID-X1) received autologous CD34+ hematopoietic cells following ex vivo gene transfer using a retroviral vector, with subsequent demonstration of improved immune responses. A number of preclinical and clinical studies have been conducted with the aim of developing gene therapy for hemophilia, Fanconi anemia, sickle cell disease, beta-thalassemia, chronic granulomatous disease, and other inherited hematological disorders. The greatest advances in novel approaches toward treatment of hematological disorders have been made in hemophilia, with 3 current phase I clinical trials ongoing. Two trials are investigating the safety and feasibility of utilizing either an ex vivo, non-viral gene transfer technique or an intravenous infusion of a retroviral vector to treat adults with severe hemophilia A (factor VIII deficiency). The third study involves intramuscular administration of an adeno-associated viral (AAV) vector for expression of factor IX in adult patients with hemophilia B. Results from this study and from preclinical studies preceding the trial demonstrate that it is possible to safely administer high doses of a viral vector in vivo.