Soy Phosphatidylinositol–Containing Lipid Nanoparticle Prolongs the Plasma Survival and Hemostatic Efficacy of B-domain–Deleted Recombinant Canine Factor VIII in Hemophilia A Dogs

Abstract

Soy phosphatidylinositol (PI) containing lipid nanoparticles prolong plasma survival, improve hemostatic efficacy, and decrease immunogenicity of human B-domain deleted Factor VIII (BDD FVIII) in Hemophilia A (HA) mice. We hypothesize that PI associated BDD FVIII is more potent than the free protein, and using mathematical modeling, have projected that PI associated BDD FVIII could be used for once-weekly prophylactic dosing in patients. To facilitate translation to the clinic, comparative plasma survival and ex vivo efficacy of PI associated recombinant canine FVIII (PI-rcFVIII) were evaluated in HA dogs. 2 HA dogs were administered a 50 U/kg iv dose of free or PI-rcFVIII. rcFVIII activity measurements and ex vivo efficacy analyses like whole blood clotting time (WBCT) and thromboelastography (TEG) were conducted on recovered plasma and whole blood samples. PI association decreased clearance (~25%) and increased plasma exposure (~1.4 fold) of rcFVIII. PI-rcFVIII treated animals had prolonged improvements in WBCTs and TEG parameters compared to free rcFVIII treated animals. Since rcFVIII is a BDD form of FVIII, these studies provide proof-of-principle that observations with human BDD FVIII in mice translate to higher animal species. Additionally, PI-rcFVIII has potential applications in canine HA management and as a bypass therapy in inhibitor-positive HA patients.

An Observational Study from Long-Term AAV Re-administration in Two Hemophilia Dogs

“…The signal intensities from regions of interest were expressed as total photon flux (photons per second), which has been used widely in studies. 51 , 52 …”

Nanoparticles for hematologic diseases detection and treatment

“…Liposomes can encapsulate drugs for different medical purposes: thrombin inhibitors, able to exert an anticoagulant activity in case of arterial acute thrombosis [ 136 ], mRNA to encode erythropoietin, factor IX protein [ 137 ] and anti-factor VIII antibodies [ 138 , 139 ] for haemophilia treatment and Tmprss6 siRNA for thalassemia cure [ 140 ].…”

An overview on the investigation of nanomaterials' effect on plasma components: immunoglobulins and coagulation factor VIII, 2010–2020 review

“…Moreover, joined researches represented the efficacy of using B-domain deleted (BDD)-rFVIII conjugated soy phosphatidylinositol lipidic nanoparticles in reducing inhibitory development and 1.5-fold extend and 1.4-fold increase in terminal half-life of BDD-rFVIII to 18 hours in mice clinical trials and dogs, respectively. Simultaneously, the immunogenicity assay has been evaluated in the presence of labeled anti IgG as well (59)(60)(61). Furthermore, in similar research in 2018, it has been demonstrated that subcutaneous administration of Lys-phosphatidylserine could extend the half-life to 1.6 fold by reducing the immunogenicity (62).…”