Design and characterization of an APC-specific serpin for the treatment of hemophilia

Polderdijk, Stéphanie G. I.; Adams, Ty E.; Ivanciu, Lacramioara; Camire, Rodney M.; Baglin, Trevor; Huntington, James A.

doi:10.1182/blood-2016-05-718635

Cited by 130 publications

(135 citation statements)

References 52 publications

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“…These data suggest that EPCR-mediated APC anticoagulant pathway plays a critical role in modulating thrombin generation in hemophilia and inhibition of APC anticoagulant pathway can balance the deficiency in the procoagulant pathways in hemophilia. Recent observations that showed inhibition of APC with a variant of α1-antitrypsin 21 or specific antibody 22 restored hemostasis in mouse and monkey bleeding model systems, respectively, are consistent with the above concept. The ability of super FVa (FVa resistant to APC inactivation) to correct the blood loss in hemophilia mice 23 also supports the above concept.…”

Section: Discussionsupporting

confidence: 67%

Factor VIIa interaction with EPCR modulates the hemostatic effect of rFVIIa in hemophilia therapy: mode of its action

et al. 2017

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Recent studies established that clotting factor VIIa (FVIIa) binds endothelial cell protein C receptor (EPCR). It has been speculated that FVIIa interaction with EPCR might augment the hemostatic effect of rFVIIa in therapeutic conditions. The present study is carried out to investigate the mechanism by which FVIIa interaction with EPCR contributes to the hemostatic effect of rFVIIa in hemophilia therapy. Active-site inhibited FVIIa, which is capable of binding to EPCR but has no ability to activate factor X, reduced the concentration of rFVIIa required to correct the bleeding following the saphenous vein injury in mouse hemophilia model systems. Higher doses of rFVIIa were required to restore hemostasis in EPCR overexpressing hemophilia mice compared to hemophilia mice expressing normal levels of EPCR. Administration of FVIII antibody induced only mild hemophilic bleeding in EPCR-deficient mice, which was corrected completely with a low dose of rFVIIa. Administration of therapeutic concentrations of rFVIIa increased plasma protein C levels in EPCR overexpressing mice, indicating the displacement of protein C from EPCR by rFVIIa. EPCR levels did not significantly alter the bioavailability of rFVIIa in plasma. Overall, our data indicate that EPCR levels influence the hemostatic effect of rFVIIa in treating hemophilia. Our present findings suggest that FVIIa displacement of anticoagulant protein C from EPCR that results in down-regulation of activated protein C generation and not the direct effect of EPCR-FVIIa on FX activation is the mechanism by which FVIIa interaction with EPCR contributes to the hemostatic effect of rFVIIa in hemophilia therapy.

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Section: Discussionsupporting

confidence: 67%

Factor VIIa interaction with EPCR modulates the hemostatic effect of rFVIIa in hemophilia therapy: mode of its action

et al. 2017

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“…Targeting the anticoagulant effect of APC has also restored hemostasis in hemophilia mouse models. 47,48 NFTs appear to be able to improve hemostasis in hemophilia patients, likely including those with inhibitors; however, they do not currently appear to be able to prevent all bleeding. The experience with emicizumab should engender caution about the potential for thrombotic consequences especially when combining therapies.…”

Section: Nftsmentioning

confidence: 98%

Novel approaches to hemophilia therapy: successes and challenges

Arruda

Doshi

Samelson-Jones

2017

Blood

101

106

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New therapies for hemophilia A and hemophilia B will likely continue to change clinical practice. Ranging from extended half-life to nonfactor products and gene therapy, these innovative approaches have the potential to enhance the standard of care by decreasing infusion frequency to increase compliance, promoting prophylaxis, offering alternatives to inhibitor patients, and easing route of administration. Each category has intrinsic challenges that may limit the broader application of these promising therapies. To date, none specifically address the challenge of dispersing treatment to the developing world.

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“…A few serpin-related bleeding disorders are known: α1-PI Pittsburgh has a Met358Arg mutation in its reactive site, which shifts its specificity from elastase to thrombin, thereby impairing normal blood clotting; and congenital α2-antiplasmin deficiency results in premature lysis of hemostatic plugs by excess plasmin. Selective inhibition of the anticoagulant activated protein C by mutating the reactive site-flanking residues of α1-PI Pittsburgh to lysines has been shown successful in normalizing bleeding in a hemophilia B mouse model, and may show promise as a novel hemophilia drug [113]. …”

Section: Proteases and Diseasementioning

confidence: 99%

Proteases: Pivot Points in Functional Proteomics

Verhamme

Leonard

Perkins

2018

Functional Proteomics

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Proteases drive the life cycle of all proteins, ensuring the transportation and activation of newly minted, would-be proteins into their functional form while recycling spent or unneeded proteins. Far from their image as engines of protein digestion, proteases play fundamental roles in basic physiology and regulation at multiple levels of systems biology. Proteases are intimately associated with disease and modulation of proteolytic activity is the presumed target for successful therapeutics. “Proteases: Pivot Points in Functional Proteomics” examines the crucial roles of proteolysis across a wide range of physiological processes and diseases. The existing and potential impacts of proteolysis-related activity on drug and biomarker development are presented in detail. All told the decisive roles of proteases in four major categories comprising 23 separate sub-categories are addressed. Within this construct, 15 sets of subject-specific, tabulated data are presented that include identification of proteases, protease inhibitors, substrates and their actions. Said data are derived from and confirmed by over 300 references. Cross comparison of datasets indicates that proteases, their inhibitors/promoters and substrates intersect over a range of physiological processes and diseases, both chronic and pathogenic. Indeed, “Proteases: Pivot Points …” closes by dramatizing this very point through association of (pro)Thrombin and Fibrin(ogen) with: hemostasis, innate immunity, cardiovascular and metabolic disease, cancer, neurodegeneration and bacterial self-defense.

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Design and characterization of an APC-specific serpin for the treatment of hemophilia

Abstract: Key Points The endogenous inhibitors of APC also inhibit other coagulation proteases rendering them unacceptable for treatment of hemophilia. Rationally designed APC-specific serpins rescue thrombin generation in vitro and restore hemostasis in hemophilia mouse models.

Cited by 130 publications

References 52 publications

Factor VIIa interaction with EPCR modulates the hemostatic effect of rFVIIa in hemophilia therapy: mode of its action

Factor VIIa interaction with EPCR modulates the hemostatic effect of rFVIIa in hemophilia therapy: mode of its action

Novel approaches to hemophilia therapy: successes and challenges

Proteases: Pivot Points in Functional Proteomics

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