FVIIa gene delivery: potential treatment for hemophilia?

Hemophilia A and B are severe Xlinked inherited bleeding disorders caused by deficiency of blood coagulation factors (F) VIII and FIX, respectively. Currently, hemophilia is treated with protein replacement therapy using either plasma-derived or recombinant coagulation factors. Although replacement therapy is extremely effective and has significantly enhanced the quality and life expectancy of patients with hemophilia, a number of challenges still remain. Significantly, some patients develop neutralizing (or inhibitor) antibodies after replacement therapy, resulting in the clinical failure of standard replacement treatment; 20% to 30% of patients with severe hemophilia A and about 5% with severe hemophilia B. Patients who have developed such antibodies may undergo immune tolerance therapy; however, this is very expensive and may not be effective. Inhibitor patients may be treated with “bypass” agents, such as activated prothrombin complex concentrate, but this has a low efficacy and has an associated thromboembolic risk. More recently, recombinant (r) FVIIa (NovoSeven) has been a highly successful treatment for hemophilia inhibitor patients. rFVIIa is believed to produce a “thrombin burst” on the surface of activated platelets, leading to activation of FIX and FX in a tissue factor–independent mechanism. rFVIIa can thus be used to treat both hemophilia A and B patients with inhibitors. However, although rFVIIa is effective, it is extremely expensive because of the large dose required for efficacy and the short halflife of 2.7 hours. There have been major advances in gene therapy for hemophilia, particularly in vector design, that have resulted in sustained therapeutic expression in mice, hemophilic dogs, and nonhuman primates. However, as the Scottish poet Robert Burns noted in his poem, “To a Mouse,” “the best laid schemes of mouse and man often go askew.” So results from rodent species have not always translated to larger animals with quite the same efficacy. Thus, a safe, effective gene therapy treatment for hemophilia in humans has not yet been realized. Treating hemophilia inhibitor patients with gene therapy that will lead to expression of a protein to which these patients have preexisting antibodies is a complex issue. Two alternative approaches to tackle this problem have been studied: in one, the expression of the replacement factor (FVIII) has been targeted to the -granules of platelets. Thus, the FVIIa walks a tightrope balancing hemostasis and thrombosis. Professional illustration by Marie Dauenheimer.