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Mutated factor X to correct hemophilias
mg/kg) in wild-type rabbits did not lead to any sign of suf- fering suggesting that even in vivo in a blood normally prone to coagulate the molecule probably remains in the form of a zymogen (Online Supplementary Figure S2). Nevertheless, to confirm the safety of the molecule, more challenging in vivo models, such as the Wessler assay, are scheduled.
Another primary concern regarding any novel biologic is its potential to elicit an immune response. This can be investigated during product development although pre- liminary evaluations using in silico, in vitro and in vivo mod- els are recognized to be not fully predictive.30-32 Nevertheless, actiten was assessed by three independent in silico algorithms, and none identified any specific con- cern for its immunogenicity in comparison to that of pdFX (data not shown).
Emicizumab is the most advanced NRF and has some
crucial advantages for patients, in particular for those who have developed inhibitors.14 However, some patients treated with this compound still experienced bleeding whereas others developed anti-drug antibodies. Thus, there is still a need for alternative therapies with different mechanisms of action to improve patients’ care. The in vitro and in vivo data presented here validate the concept of re-directing the FX specificity to bypass the need for FVIII and FIX and may offer an additional opportunity to correct bleeding in several coagulation defects even in the presence of inhibitors.
Acknowledgments
The authors thank Bianca Boussier, Sylvie Le Ver, Bénedicte Fournes and Paul Martres for their participation in the in vivo experiments, Sophie Lecompte for helping to correct the manu- script and Céline Bourdon for her technical help.
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