Gene therapy is an attractive approach for the treatment of hemophilia, as continuous expression of donated clotting factor VIII (FVIII) DNA would ensure clotting factor replacement at constant circulating levels rather than at the peaks and troughs that characterize the current protein infusion therapeutic approach. In this issue of the JCI, Shi et al. describe an interesting variant of a gene transfer approach for hemophilia (see the related article beginning on page 1974). They show that targeted expression of FVIII in megakaryocytes, with storage in the α-granules of platelets, has the advantage of delivering clotting factors directly to the site of an injury, where platelets accumulate in large numbers and undergo activation accompanied by release of granule contents. Earlier clinical experience with gene transfer into hematopoietic cells highlighted the potential safety risks of this approach, but an F8 transgene may represent a lower risk than transgenes for growth factors or their receptors.
Katherine A. High
Strategies for achieving long-term protein expression in genetic disease.