In vivo gene transfer moves one step closer to success

Achieving sustained expression of clotting factors and achieving this expression at levels high enoughto result in clinical improvement have been the two critical goals of efforts to treat hemophilia by gene transfer. In this issue Nathwani and colleagues (page 1662) demonstrate that they have achieved this goal, long-term expression of therapeutic levels of factor IX (4%-10% of normal levels in humans), by administration of a recombinant AAV vector into the hepatic circulation of Rhesus macaques. These data are in fairly close agreement with work published just weeks earlier by Mount et al (Blood. 2002;99:2670-2676), reporting similar findings in hemophilic dogs treated by portal-vein infusion of a recombinant AAV vector. Certainly, it is encouraging to see similar results and excellent safety profiles in 2 different large-animal models, and the current study lends further support to an ongoing clinical trial of hepatic artery infusion of rAAV in patients with hemophilia B (http://www4.od.nih.gov/oba/rac/trialquery.asp?C1=1&diseasename=25). But as is often the case in cutting-edge investigation, this study raises at least as many questions as it answers: the relationship between vector dose and factor IX levels; the effect of pre-existing antibodies to the vector capsid on gene transfer; and the relative efficacy of portal vein versus hepatic artery administration, to list but a few. (The study is of less utility in assessing immune response to the transgene product since the authors used a humanfactor IX vector in Rhesus macaques.) This study also underscores the difficulties inherent in attempting to answer critical questions through the use of large animals as opposed to mice: though one gains in terms of a more accurate model of the human species, one loses in terms of numbers of animals in each experiment.

Proof of principle for ex vivo clinical gene transfer was established 2 years ago by the groundbreaking work of CavazzanoCalvo et al in infants with X-linked SCID (Science. 2000;288:669-672). Convincing evidence in support of in vivo gene transfer has been more elusive. With this study, the goal of developing “gene medicine in a bottle” comes one step closer to reality.