Gene Therapy for Severe Hemophilia A

A family medicine physician cares for a family in which both the grandfather and young grandson have hemophilia A. Recently, the grandfather came for a check-up on his arthritis and asked the physician, “Is there anything new for hemophilia that can help my grandson avoid what I’ve been through over the years? I wish there was some way he could avoid all those factor VIII infusions, the breakthrough bleeding, and all the painful joint damage.”

Patients with hemophilia A require frequent prophylactic infusions of factor VIII — on average 3 times per week — to prevent bleeding in joints, soft tissue, and the central nervous system. Unfortunately, breakthrough bleeding with progressive joint destruction and pain is common and can further impair quality of life. In addition, approximately one-third of patients develop antibodies to factor VIII that block its therapeutic effects. Gene transfer first showed promise in the treatment of hemophilia B, but the large size of the factor VIII gene has delayed the development of gene therapy for hemophilia A.

In this week’s issue of NEJM, Rangarajan et al. report the results of a single intravenous infusion of adeno-associated virus (AAV) factor VIII in nine adult men with severe hemophilia A. Patients were enrolled sequentially to low-dose (1 patient), intermediate-dose (1 patient), or high-dose (7 patients) cohorts and were followed for 52-weeks. Patients who received lower doses were escalated to a higher dose if their factor VIII levels were inadequate and safety requirements were maintained. High-dose patients were also treated with a short course of glucocorticoids to minimize liver toxicity from the virus.

In the low- and intermediate-dose cohorts, factor VIII levels remained low (≤3 IU/dL). However, in all seven patients in the high-dose cohort, the factor VIII level increased to the cut-off level for mild-to-moderate hemophilia (>5 IU/dL) between weeks 2 and 9; the factor VIII level in six patients increased to a normal value (>50 IU/dL) that was maintained at 1 year. In the high-dose cohort, the median annualized bleeding rate decreased from 16 events before the study to 1 event after gene transfer, and factor VIII use for bleeding ceased in all the participants in this cohort by week 22. Adverse events related to the gene therapy were considered minor. Seven patients experienced mild elevation in serum alanine aminotransferase (ALT) levels that resolved without sequelae. One patient experienced progression of pre-existing chronic arthropathy.

The authors concluded that in this small study of nine patients with severe hemophilia A, a single infusion of the high-dose vector-encoded factor VIII led to sustained normalization of factor VIII activity, with significant reduction in bleeding events and additional factor VIII use. Although no serious adverse events were reported during the 1-year study, further testing in more patients with longer follow-up is needed to determine the efficacy and safety of this novel treatment.

Returning to the patient’s question, although research on gene therapy for hemophilia A requires further study before it becomes widely available, hope is on the horizon that the patient’s grandson will be able to receive treatment to prevent the complications of hemophilia A and significantly improve his quality of life.

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Karen is a 2017-2018 NEJM Editorial Fellow, Clinical Professor at UC Berkeley-UCSF Joint Medical Program and UC Berkeley School of Public Health, researcher on children’s nutrition and oral health, and member of American Academy of Pediatrics.