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Binding of Factor VIII to Lipid Nanodiscs Increases its Clotting Function in a Mouse Model of Hemophilia A.

ABSTRACT: BACKGROUND:Hemophilia A is a congenital bleeding disorder caused by defective or deficient factor VIII (FVIII). The active form of FVIII is the co-factor for the serine protease factor IXa (FIXa) in the membrane-bound intrinsic tenase (FVIIIa-FIXa) complex. The assembly of the FVIIIa-FIXa complex on the activated platelet surface is critical for successful blood clotting. OBJECTIVES:To characterize the role of lipid nanodiscs (ND) for on FVIII function in vivo and test the lipid ND as a delivery system for FVIII. To evaluate the potential of binding recombinant FVIII to ND as improved treatment for Hemophilia A. METHODS:Recombinant porcine FVIII (rpFVIII) was expressed and characterized in solution, and when bound to ND. The rpFVIII, ND and rpFVIII-ND complexes were characterized via transmission electron microscopy. Functional studies were carried out using aPTT tests and time resolved tail snip studies of hemophilic mice. RESULTS:Functional rpFVIII was successfully assembled on lipid ND. When injected in hemophilic mice, the rpFVIII-ND complexes showed a pronounced pro-coagulant effect, which was stronger than that of rpFVIII alone. While injection of the ND alone showed a pro-coagulant effect this effect was not additive, implying that the rpFVIII-ND complexes have a synergistic effect on the clotting process in hemophilic mice. CONCLUSIONS:Binding of rpFVIII to ND prior to its injection in hemophilic mice significantly improves the therapeutic function of the protein. This represents a meaningful step towards a new approach to modulate blood coagulation at the membrane-bound FVIII level and the assembly of the intrinsic tenase complex.

SUBMITTER: Csencsits-Smith K

PROVIDER: S-EPMC5603210 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Binding of Factor VIII to Lipid Nanodiscs Increases its Clotting Function in a Mouse Model of Hemophilia A.

Csencsits-Smith Keri K Grushin Krill K Stoilova-McPhie Svetla S

Journal of blood disorders & transfusion 20151218 6

<h4>Background</h4>Hemophilia A is a congenital bleeding disorder caused by defective or deficient factor VIII (FVIII). The active form of FVIII is the co-factor for the serine protease factor IXa (FIXa) in the membrane-bound intrinsic tenase (FVIIIa-FIXa) complex. The assembly of the FVIIIa-FIXa complex on the activated platelet surface is critical for successful blood clotting.<h4>Objectives</h4>To characterize the role of lipid nanodiscs (ND) for on FVIII function in vivo and test the lipid N ...[more]

PMID: 28936365

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Project description:Hemophilia A and B are bleeding disorders caused by a deficiency of clotting factor VIII and IX, respectively. Patients with severe hemophilia (< 0.01 IU mL-1) and some patients with moderate hemophilia (0.01-0.05 IU mL-1) administer clotting factor concentrates prophylactically. Desmopressin (D-amino D-arginine vasopressin) can be applied in patients with non-severe hemophilia A. The aim of administration of factor concentrates or desmopressin is the prevention or cessation of bleeding. Despite weight-based dosing, it has been demonstrated that factor concentrates still exhibit considerable pharmacokinetic variability. Population pharmacokinetic analyses, in which this variability is quantified and explained, are increasingly performed in hemophilia research. These analyses can assist in the identification of important patient characteristics and can be applied to perform patient-tailored dosing. This review aims to present and discuss the population pharmacokinetic analyses that have been conducted to develop population pharmacokinetic models describing factor levels after administration of factor VIII or factor IX concentrates or D-amino D-arginine vasopressin. In total, 33 publications were retrieved from the literature. Two approaches were applied to perform population pharmacokinetic analyses, the standard two-stage approach and non-linear mixed-effect modeling. Using the standard two-stage approach, four population pharmacokinetic models were established describing factor VIII levels. In the remaining 29 analyses, the non-linear mixed-effect modeling approach was applied. NONMEM was the preferred software to establish population pharmacokinetic models. In total, 18 population pharmacokinetic analyses were conducted on the basis of data from a single product. From all available population pharmacokinetic analyses, 27 studies also included data from pediatric patients. In the majority of the population pharmacokinetic models, the population pharmacokinetic parameters were allometrically scaled using actual body weight. In this review, the available methods used for constructing the models, key features of these models, patient population characteristics, and established covariate relationships are described in detail.

Dataset Information

Binding of Factor VIII to Lipid Nanodiscs Increases its Clotting Function in a Mouse Model of Hemophilia A.

Publications

Binding of Factor VIII to Lipid Nanodiscs Increases its Clotting Function in a Mouse Model of Hemophilia A.

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