Tentative progress in hemophilia B gene therapy

In 1999 investigators at the University of Pennsylvania and Stanford University began a trial in which intramuscular AAV–factor IX injections were given to hemophilia B patients. Two of the first 3 patients (treated with 2 × 10¹¹ vector genomes/kg) demonstrated a therapeutic increment of factor IX (about 1% of normal factor IX activity) with little or no toxicity (Kay et al, Nat Genet. 2000;24:257-261). It was anticipated that higher levels of factor IX would be achieved as the vector dose was increased.

In this issue, Manno and colleagues (page 2963) report the final results of this trial, including long-term follow-up of the first group and 2 additional cohorts who received 3- and 9-fold greater vector doses. Unfortunately, the higher-dose groups have failed to improve on these factor IX levels. Analysis of injection site biopsies demonstrated persistence of the AAV vector, and factor IX appears in and around transduced cells; so delivery of factor IX to the circulation appears to be the issue. Until the amount of transduced muscle is sufficient to overcome local factor IX binding, plasma factor IX levels will not reflect a dose-dependent relationship. The original study design contemplated higher doses than were eventually used, but these plans were scaled back following the Jesse Gelsinger tragedy, as a precautionary measure. It seems unlikely at this point that levels above 1% could be achieved by further dose escalation since the volume and number of intramuscular injections becomes impractical. It is reassuring, nevertheless, that no major toxicity of AAV–factor IX gene transfer has emerged from this study, and most importantly no inhibitor antibodies to factor IX were seen.

What comes next? Animal studies predict that factor IX expression directed by a liver-specific promoter may be advantageous. A clinical trial to test liver-targeted AAV–factor IX gene transfer has now been initiated by these investigators, and we will also look forward to its results with great anticipation. (This commentary does not indicate US government policy.)