Hemophilia gene transfer: comparison with conventional protein replacement therapy

One of the unanswered questions in hemophilia is whether gene transfer, if successful, will be a safe and effective alternative to standard clotting factor treatment for hemophilia. Despite life-threatening complications of protein-based clotting factor treatment during the last three decades, including acquired immunodeficiency syndrome and hepatitis C, factor infusion is now considered safe, effective, and compatible with a normal lifespan. Thus, protein-based therapy will be the standard against which the safety and efficacy of gene transfer will be judged. Will the potential risks of gene transfer be sufficiently low to justify its use? Should all individuals with hemophilia consider gene transfer? To answer these questions, the known risks and benefits of current protein-based therapy must be compared with the potential risks and benefits of gene transfer. It is anticipated that risks of gene transfer may include the known risks of protein-based therapies, including allergic reactions, inflammatory responses, inhibitor formation, chronic hepatitis, as well as gene-transfer-specific risks, including germline transmission, insertional mutagenesis, thrombosis, and potential ethical and psychological issues. This article reviews and compares the risks and benefits of standard protein-based therapy with those of gene transfer, and considers how gene transfer might fit into state-of-the-art management of hemophilia.