Gene therapy for Fanconi anemia: one step closer to the clinic.

Abstract

Game-changing trends in biomedical science usually start as daring, visionary ideas that struggle through the confusion of trials and experiments, experience a crisis at the collision of an expectant public and disbelieving colleagues, and—if successful—finally emerge as widely accepted new standards (Evans, 2011). The gene therapy field has followed this sequence and, in the teens of the twenty-first century, seems to be emerging as a realistic new therapy for genetic disorders of hematopoiesis, such as congenital immunodeficiencies and bone marrow failure syndromes (Naldini, 2011; Sheridan, 2011). Fanconi anemia (FA) is a prototypical inherited bone marrow failure disorder characterized by aplastic anemia and a dramatically increased risk of hematological and solid malignancies. FA is due to defects in one of at least 15 genes that encode the proteins involved in the cellular response to DNA damage and the maintenance of genomic integrity. More than half of the reported cases of FA are due to FANCA gene mutations. FANCA protein is a member of a ‘‘functional core complex’’ (formed with seven other proteins) that is essential in the DNA damage response. A lack of core complex results in a phenotype characterized by bone marrow failure, myelodysplasia, leukemia, and other cancers (D’Andrea, 2010). With support from the FA Research Fund and Fanconi Hope Charitable Trust, two dozen scientists and clinicians convened in Barcelona on November 22, 2011 for the second meeting of the FA Gene Therapy International Work Group. This International Work Group, chaired by Jakub Tolar (University of Minnesota, Minneapolis, MN), has been established with the goal of coordinating the best available knowledge in gene therapy with the best format of clinical trial for FA. The first meeting, a year ago in London, brought together researchers from fields that rarely interact. The objective of that meeting was to establish an open platform whereby teams initiating gene therapy trials in FA, institutions that already have strong track records in gene therapy, and groups that are developing novel strategies in genome modification could be brought together. We found common ground in our efforts to accelerate the transition of gene therapy research into clinical trials for patients with FA. The initial FA gene therapy platform was outlined as follows: FANCA gene delivered by third-generation lentiviral vector pseudotyped with vesicular stomatitis virus (VSV-G); short transduction without prolonged prestimulation with growth factors; and exclusion of individuals who have a human leukocyte antigen-matched sibling donor, an abnormal karyotype, or a serious infection (Tolar et al., 2011). The particular focus of this year’s event was to synthesize the data to inform the impending clinical trials and make the future iterations of FA gene therapy trials possible. Hematopoietic stem cell gene therapy has the potential to transform conventional therapy for FA, which for decades has involved transfusion support, anabolic steroids, and hematopoietic cell transplantation (HCT). Androgens can