Gene therapy could provide a lasting cure for several X-linked genetic disorders, including hemophilia. Currently, no curative therapies have been approved by the US Food and Drug Administration (FDA) for use in patients with hemophilia A or B. However, some promising gene therapies for these patients have recently begun phase 3 clinical trials.

In recent years, numerous preclinical and clinical studies have shown that gene transfer through the use of adeno-associated viral (AAV) vectors holds the greatest possibility of correcting deficiencies in factor VIII and IX, which lead to hemophilia A and B, respectively. In a recent review article published in Blood, George Q Perrin, PhD, of the department of pediatrics at the University of Florida in Gainesville, and colleagues provided an update on recent innovations and ongoing development of clinical gene therapies for patients with hemophilia.

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“There is a need for alternative cost-effective therapies with reduced risk and improved efficacy for hemophilia,” the researchers wrote. “Gene therapy could provide a significant benefit by providing a continuous source of clotting factor from a single treatment.”

Immunology of Clinical Gene Therapy

Although gene therapy has the potential to treat many diseases, hemophilia is particularly suitable for this method of treatment because of unique effects at the molecular level. In particular, both factor VIII and IX can be produced in nonnative tissues, which offers the possibility of correcting bleeding complications via gene delivery to cells other than hepatocytes because factor coagulation proteins are also present in the circulation. As a result, different bleeding phenotypes may respond to multiple factor levels, and specific regulation is not required.

AAV vectors are derived from a member of the parvovirus family that is a relatively nonimmunogenic, nonpathogenic, and replication-incompetent virus. These vectors act as a transgene delivery system and are capable of delivering a transgene into both dividing and nondividing cells. However, most AAV vector genomes do not integrate into the host genome, and ongoing delivery produces gradual loss of the transgene.

Several novel AAV-based gene delivery systems are currently being studied in animal models. Although initial findings are promising, the applicability of these systems for use in humans needs to be validated.

AAV Clinical Trials for Hemophilia A and B

Numerous AAV gene therapy clinical trials are underway investigating the use of various agents in patients with both hemophilia A and B. A recent search of the ClinicalTrials.gov database showed 20 active clinical studies evaluating AAV-based gene therapies, including 10 active trials each for hemophilia A and B, respectively. Several phase 3 trials are included among these studies, but the results have not yet been reported.