Hemophilia affects nearly 200,000 individuals worldwide and an estimated 20,000 people in the United States.1,2 Patients with hemophilia face multiple psychological, financial, and other challenges, including various issues associated with the management of the disease.3,4 Currently, the standard treatment approach involves frequent prophylactic self-infusion of factor VIII or IX.

“[Although] extended half-life products may reduce the frequency of injections, patients continue to face lifelong burden of the therapy, suboptimal protection from bleeding and joint damage, and potential development of neutralizing antidrug antibodies (inhibitors) that require less efficacious bypassing agents and further reduce quality of life,” wrote John SS Butterfield, of the University of Florida, and colleagues in a recent review published in Molecular Therapy that discussed recent advancements in gene therapy research.5

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These concerns underscore the need for novel treatment strategies in order to improve outcomes and quality of life for patients with hemophilia. Evidence from recent research has demonstrated the promise of gene therapy using recombinant adeno-associated viral (rAAV) vectors for the transduction of factor VIII or factor IX hepatocytes.4

“Hemophilia is a monogenic disease with robust clinicolaboratory correlations of severity,” wrote Gabriela G Yamaguti-Hayakawa, MD, and Margareth C Ozelo, MD, PhD, in a review article published in Seminars in Thrombosis and Hemostasis.6 “These attributes coupled with the availability of experimental animal models have made it an attractive model for gene therapy.”

In preclinical and clinical trials, AAV vectors have shown sustained expression of factor activity in the normal ranges. Results from the first successful trial involving peripheral infusion of the rAAV8-FIX vector were published in 2008. In 10 patients with hemophilia B, a dose-response relationship was noted: With low-dose (2 x 1011 vector genomes [vg]/kg) and intermediate-dose (6 x 1011 vg/kg) vectors, factor IX activity ranged from 1.4% to 2.9% of normal levels, compared with factor IX activity of 2.9% to 7.2% in the high-dose group (2 x 1012 vg/kg).6

More recently, 9 patients with severe hemophilia A received the single-stranded B domain-deleted factor VIII (BDD-FVIII) transgene with rAAV5. Through 1 year of follow-up, 6 of 7 participants who received higher doses of the vector demonstrated persistent factor VIII activity above 50 IU/dL, and all 7 participants showed stabilization of hemostasis and significant reductions in factor VIII use.6

In addition, a 2017 trial examined the efficacy of a liver-directed rAAV-mediated gene therapy, SPK-9001, in 10 patients with hemophilia B who received a single vector dose of 5 x 1011 vg/kg. After 28 to 78 weeks of follow-up, all participants showed sustained factor IX coagulant activity ranging from 14% to 81% of normal levels, as well as reduced bleeding and factor use.6