The leak stops here: platelets as delivery vehicles for coagulation factors
Katherine A. High
Katherine A. High
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Commentary

The leak stops here: platelets as delivery vehicles for coagulation factors

Abstract

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.

Authors

Katherine A. High

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Figure 1

Strategies for achieving long-term protein expression in genetic disease.

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Strategies for achieving long-term protein expression in genetic disease...
(A) Gene transfer strategies leading to long-term protein expression in canine hemophilia. At left, intravenous infusion of a retroviral vector expressing canine factor IX (FIX) into neonatal dogs results in transduction of hepatocytes with transmission of the integrated DNA into all daughter cells and continuous expression of factor IX in the growing animal (1). In the approach shown to the right, with portal vein infusion of adeno-associated virus–FVIII (AAV-FVIII) or –factor IX into an adult animal, the donated DNA is stabilized in an episomal form, with long-term expression of the clotting factor (2–4). (B) After gene transfer into hematopoietic stem cells (CD34+ cells), megakaryocytes carrying the donated gene give rise to platelets that contain FVIII packaged in the α-granules. Activation of platelets at the site of an injury leads to release of granule contents, including FVIII.