دانلود رایگان مقاله انگلیسی درمان ژن هدفمند پلاکت برای بیماری هموفیلی - الزویر 2018

Gene therapy is an attractive approach for disease treatment. Since platelets are abundant cells circulating in blood with the distinctive abilities of storage and delivery and fundamental roles in hemostasis and immunity, they could be a unique target for gene therapy of diseases. Recent studies have demonstrated that ectopic expression of factor VIII (FVIII) in platelets under control of the platelet-specific promoter results in FVIII storage together with its carrier protein von Willebrand factor (VWF) in a-granules and the phenotypic correction of hemophilia A. Importantly, the storage and sequestration of FVIII in platelets appears to effectively restore hemostasis even in the presence of functional-blocking inhibitory antibodies. This review summarizes studies on platelet-specific gene therapy of hemophilia A as well as hemophilia B.

The Safety Issues and Perspective in Platelet Gene Therapy

Several safety issues should be considered while conducting any platelet-specific gene therapy protocol for hemophilia A. Since FVIII is not normally expressed in platelets and platelets play fundamental roles in both hemostasis and thrombosis, it is important to evaluate whether ectopic expression of FVIII in platelets would have a potential thrombotic risk. To evaluate this critical safety issue, several new lines of 2bF8 transgenic mice (LV17tg, LV18tg, and LV17/18tg) 51,52 were generated using 2bF8 lentivirus-mediated transgenesis in an effort to establish a line with a high level of platelet-FVIII. Baumgartner and colleagues51 used a line, LV17/18tg, that expresses 30-fold higher platelet-FVIII levels than therapeutically required to restore hemostasis in hemophilic mice to assess the hemostatic properties of platelet-FVIII with a variety of techniques, including native whole-blood thrombin generation, ex vivo and in vivo clot formation, assessment of plasma parameters associated with increased thrombosis risk (D-dimer, thrombin anti-thrombin complexes, fibrinogen), tissue fibrin deposition, platelet activation status and activatability, and evaluation of platelet-leukocyte aggregates. Their data demonstrated that in steady state as well as under prothrombotic conditions induced by lipopolysaccharides (LPS)-mediated inflammation or the factor V Leiden mutation, supratherapeutic levels of platelet-FVIII appeared nonthrombogenic. Furthermore, FVIII-expressing platelets were neither hyperactivated nor hyperactivatable upon agonist activation.