Treatment of a Hemophilia B Mouse Model with Platelet-Targeted Expression of Factor IX Padua.

Targeting the coagulation factor IX (FIX) expression in platelets has been shown to be effective in ameliorating bleeding in hemophilia B (HB) mice. To improve the therapeutic effects and evaluate the safety of this gene therapy strategy, we generated a transgenic mouse model on an HB background with FIX Padua target expressed in platelets. The transgenic mice exhibited stable expression and storage of FIX Padua in platelets. The platelet-stored FIX Padua could be released with the activation of platelets, and the proportion of platelet-stored FIX Padua in whole blood was the same as that of platelet-stored wild-type human FIX. The platelet-derived FIX Padua showed substantially increased specific activity compared with wild-type FIX. Reduced bleeding volume in the FIX Padua transgenic mice demonstrated that bleeding in the mice was improved. Levels of thrombin-antithrombin complex, fibrinogen, D-Dimer, and blood cell counts were normal in the transgenic mice, suggesting that thrombotic risk was not increased in this mouse model. However, the leakage and failure to overcome the presence of inhibitor to wild-type FIX is also observed with FIX Padua, as expected. Taken together, our results support the conclusion that targeting FIX Padua expression in platelets may be an effective and safe gene therapy strategy for HB, and could provide an ideal model to evaluate the safety of platelet-targeted gene therapy for treating hemophilia.