Coagulation Factor VIII: Biological Basis of Emerging Hemophilia A Therapies

凝结 止血 血管性血友病因子 遗传增强 医学 因子IX 免疫原性 免疫学 双特异性抗体 重组DNA 抗体 生物 内科学 血小板 基因 遗传学 单克隆抗体
作者
Ben Samelson-Jones,Lindsey A. Greene,Bhavya S. Doshi
出处
期刊:Blood [American Society of Hematology]
标识
DOI:10.1182/blood.2023023275
摘要

Coagulation factor (F) VIII is essential for hemostasis. After activation, it combines with activated FIX (FIXa) on anionic membranes to form the intrinsic tenase enzyme complex, responsible for activating FX in the rate-limiting step of sustained coagulation. Hemophilia A and hemophilia B are due to inherited deficiencies in the activity of FVIII and FIX, respectively. Treatment of hemophilia A over the last decade has benefited from improved understanding of FVIII biology, including its secretion pathway, its interaction with von Willebrand factor in circulation, the biochemical nature of its FIXa cofactor activity, the regulation of FVIIIa by inactivation pathways, and its surprising immunogenicity. This has facilitated biotechnology innovations with first-in-class examples of several new therapeutic modalities recently receiving regulatory approval for hemophilia A, including FVIII mimetic bispecific antibodies and recombinant adeno associated viral (rAAV) vector-based gene therapy. Biological insights into FVIII are also guiding the development and use of gain-of-function FVIII variants aimed at addressing limitations of first-generation rAAV vectors for hemophilia A. Several gain-of-function FVIII variants designed to have improved secretion are currently incorporated in second-generation rAAV vectors and have recently entered clinical trials. Continued mutually reinforcing advancements in the understanding of FVIII biology and treatments for hemophilia A will be necessary to achieve the ultimate goal of hemophilia therapy: normalizing hemostasis and optimizing well-being with minimal treatment burden for all patients worldwide. -
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