Gene Therapy for Hemophilias: Opportunities and Challenges for the Clinical Laboratory

Hemophilia A and B are X-linked coagulation disorders characterized by low or dysfunctional Factor VIII (FVIII) or IX (FIX), respectively. Currently, hemophilia A and B are treated by FVIII/FIX replacement therapy with plasma-derived or recombinant products or by FVIII-mimetic agents (e.g., emicizumab). More recently, gene therapy (GT) has been developed and licensed for use in patients.

In recent years, adeno-associated viral vectors (AAVV) have been developed as a means to transfer genetic material into liver cells. Clinical trials of patients with hemophilia A or B have shown that GT is effective at sustaining plasma levels of FVIII/FIX and reducing bleeding. Important issues must be considered with GT, including the gene, the delivery method, the target organ, and the measurement of the FVIII/IX produced thereafter.

Several conclusions can be drawn about GT in hemophilia A and B based on the literature and clinical practice. First, relevant gene material (FVIII/FIX) can be incorporated into AAVV, which is then infused into patients. AAVV targets liver cells and produces FVIII/IX. Second, the selection of patients who should be free from liver disease is paramount for successful therapy. Third transgene factors can be measured by one-stage clotting (OSA) or chromogenic assays (CA). Based on results from clinical trials, OSA measures transgene factor levels that are approximately 2 times higher than CA. Although expert opinions favor the OSA for transgene FIX and CA for transgene FVIII, no firm evidence is yet available on which method is better associated with clinical outcomes.