Blood, 15 April 2003, Vol. 101, No. 8, pp. 2903-2903
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.)
Jay Nelson Lozier
Food and Drug
Administration
