Gene Therapy for Factor IX Deficiency

In a prior report, intravenous infusion of a single dose of a factor IX transgene delivered with an adenovirus vector raised levels of factor IX for up to 16 months in six patients with hemophilia B (Christmas Disease; NEJM JW Oncol Hematol Jan 10 2012). Subsequently, the U.K. investigators administered the previous highest dose to four additional patients and now report 3-year follow-up data for all 10 participants.

Steady-state factor IX levels of 1% to 6% were reached within 4 months of infusion and remained stable for a median of 3.2 years (range, 1.5–4.3 years). Factor IX concentrations were dose-dependent, rising from 1.8% with the lowest dose to 5.1% with the highest dose. Of the seven patients previously on factor IX prophylaxis, four were able to discontinue prophylaxis, and the annual dose of factor IX concentrate for all patients declined from 2613 U/kg to 206 U/kg (P=0.03). In addition, the median annual number of bleeding episodes within the entire cohort decreased from 15.5 to 1.5; among patients in the high-dose group, the median annual number of bleeding episodes decreased from 16.5 to 1.0, a relative reduction of 94% (P=0.03).

The major adverse effect — asymptomatic elevation of alanine aminotransferase accompanied by a decline in factor IX levels — occurred 7 to 10 weeks after the infusion in four of the six patients receiving the highest dose of the transgene. This reaction was accompanied by an increase in the number of adenovirus capsid-reactive T-cells. Patients who experienced this effect responded to treatment with a tapering course of prednisolone. No patient developed neutralizing antibodies to factor IX.