A study published in the April 2009 journal Blood provides evidence to suggest that gene transfer could be used to initiate the continuous expression of activated factor VII (FVIIa) in dogs with hemophilia. Success of an experimental therapy in trials with canine models is often a stepping stone to eventual human clinical trials. The lead investigator of the study was Paris Margaritis, PhD, Division of Hematology, The Children’s Hospital of Philadelphia.
Known as a bypassing agent, FVIIa helps patients with hemophilia avoid an inhibitor response by circumventing the need for factor VIII or IX, while still achieving blood clotting. It is estimated that 20% to 30% of patients with severe hemophilia A develop inhibitors, while approximately 5% of patients with severe hemophilia B do. While immune tolerance induction can be highly successful in eliminating inhibitors, it must been given continuously for a long period, is costly and is not effective in all patients. FVIIa provides an alternative.
In the study, Margaritis and colleagues showed that a gene transfer mode of therapy could generate the regular production of FVIIa, ensuring adequate hemostasis and avoiding the production of antibodies, or inhibitors. The investigators used a viral vector, recombinant adeno-associated virus (AAV), as a vehicle to transfer the genetic material to three dogs with hemophilia A and one with hemophilia B. AAVs are considered by many scientists as optimal gene therapy vectors because they can be used to infect cells without causing disease. The material, known as a transgene, was genetically engineered to induce the production of FVIIa in the dogs’ livers. The transgene was delivered through the dogs’ hepatic portal vein, which carries blood from the digestive organs and spleen to the liver.
Study results showed the therapy was well tolerated by the dogs, who had long-term stable expression of FVIIa. In addition, clotting time was decreased and there were no incidences of spontaneous bleeding. Potential complications, such as thrombosis (excessive clotting), hepatotoxicity (injury to the liver from chemicals or drugs) and immune inhibitor response, were avoided. Drawbacks to using FVIIa are that it is costly and has a short half-life—only 2.7 hours on average.
“These data provide the first evidence for in vivo efficacy and safety of continuously expressed FVIIa as a FVIII/FIX-bypassing agent in a large animal model of hemophilia, avoiding the risk of inhibitor formation associated with bolus FVIII or FIX infusion,” reported the authors.
In future trials, larger studies will need to be conducted. Obtaining the proper level of FVIIa can be tricky. In previous studies on mice given larger doses of FVIIa, thrombosis and early mortality occurred.
Source: Margaritis P, Roy E, Aljamali M, Downey H, Giger U, Zhou S, Merricks E, Dillow A, Ezban M, Nichols T, High K. Successful treatment of canine hemophilia by continuous expression of canine FVIIa. Blood, April 16, 2009; 113 (16): 3682-3689.