Suppression of fibrin(ogen)-driven pathologies in disease models through controlled knockdown by lipid nanoparticle delivery of siRNA.

Autor:	Juang LJ; Michael Smith Laboratories.; Centre for Blood Research, and.; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada., Hur WS; Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC., Silva LM; Proteases and Tissue Remodeling Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD., Strilchuk AW; Michael Smith Laboratories.; Centre for Blood Research, and.; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada., Francisco B; Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH., Leung J; Michael Smith Laboratories.; Centre for Blood Research, and.; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada., Robertson MK; Michael Smith Laboratories.; Centre for Blood Research, and.; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada., Groeneveld DJ; Department of Pathobiology and Diagnostic Investigation, Institute for Integrative Toxicology, Michigan State University, East Lansing, MI., La Prairie B; Michael Smith Laboratories.; Centre for Blood Research, and.; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada., Chun EM; Proteases and Tissue Remodeling Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD., Cap AP; The United States Army Institute of Surgical Research, JBSA-Fort Sam Houston, TX.; Department of Medicine, Uniformed Services University, Bethesda, MD., Luyendyk JP; Department of Pathobiology and Diagnostic Investigation, Institute for Integrative Toxicology, Michigan State University, East Lansing, MI., Palumbo JS; Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH., Cullis PR; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada., Bugge TH; Proteases and Tissue Remodeling Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD., Flick MJ; Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC., Kastrup CJ; Michael Smith Laboratories.; Centre for Blood Research, and.; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.; Blood Research Institute, Versiti, Milwaukee, WI; and.; Department of Surgery, Department of Biochemistry, Department of Biomedical Engineering, and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2022 Mar 03; Vol. 139 (9), pp. 1302-1311.
DOI:	10.1182/blood.2021014559
Abstrakt:	Fibrinogen plays a pathologic role in multiple diseases. It contributes to thrombosis and modifies inflammatory and immune responses, supported by studies in mice expressing fibrinogen variants with altered function or with a germline fibrinogen deficiency. However, therapeutic strategies to safely and effectively tailor plasma fibrinogen concentration are lacking. Here, we developed a strategy to tune fibrinogen expression by administering lipid nanoparticle (LNP)-encapsulated small interfering RNA (siRNA) targeting the fibrinogen α chain (siFga). Three distinct LNP-siFga reagents reduced both hepatic Fga messenger RNA and fibrinogen levels in platelets and plasma, with plasma levels decreased to 42%, 16%, and 4% of normal within 1 week of administration. Using the most potent siFga, circulating fibrinogen was controllably decreased to 32%, 14%, and 5% of baseline with 0.5, 1.0, and 2.0 mg/kg doses, respectively. Whole blood from mice treated with siFga formed clots with significantly decreased clot strength ex vivo, but siFga treatment did not compromise hemostasis following saphenous vein puncture or tail transection. In an endotoxemia model, siFga suppressed the acute phase response and decreased plasma fibrinogen, D-dimer, and proinflammatory cytokine levels. In a sterile peritonitis model, siFga restored normal macrophage migration in plasminogen-deficient mice. Finally, treatment of mice with siFga decreased the metastatic potential of tumor cells in a manner comparable to that observed in fibrinogen-deficient mice. The results indicate that siFga causes robust and controllable depletion of fibrinogen and provides the proof-of-concept that this strategy can modulate the pleiotropic effects of fibrinogen in relevant disease models. (© 2022 by The American Society of Hematology.)
Databáze:	MEDLINE
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