RNAi targeting heparin cofactor II promotes hemostasis in hemophilia A
| Autor: | Huafang Wang, Yu Hu, Wenjuan He, Zhen Zhang, Xuan Lu, Liang Tang, Ruiqi Zhu, Wenyi Lin |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.drug_class RM1-950 Pharmacology heparin cofactor II 03 medical and health sciences 0302 clinical medicine Thrombin RNA interference Bleeding time hemic and lymphatic diseases hemophilia Drug Discovery Medicine Thrombus Heparin cofactor II medicine.diagnostic_test business.industry Anticoagulant medicine.disease thrombin 030104 developmental biology Coagulation 030220 oncology & carcinogenesis Hemostasis hemostasis Molecular Medicine Therapeutics. Pharmacology business medicine.drug Partial thromboplastin time |
| Zdroj: | Molecular Therapy: Nucleic Acids, Vol 24, Iss, Pp 658-668 (2021) |
| ISSN: | 2162-2531 |
| Popis: | Hemophilia A is a hemorrhagic disease due to congenital deficiencies of coagulation factor VIII (FVIII). Studies show that hemophilia patients with anticoagulant deficiency present less severe hemorrhagic phenotypes. We aimed to find a new therapeutic option for hemophilia patients by RNA interference (RNAi) targeting heparin cofactor II (HCII), a critical anticoagulant protein inactivating the thrombin. The optimal small interfering RNA (siRNA) was conjugated to an asialoglycoprotein receptor ligand (N-acetylgalactosamine [GalNAc]-HCII), promoting targeted delivery to the liver. After administration, GalNAc-HCII demonstrated effective, dose-dependent, and persistent HCII inhibition. After 7 days, in normal mice, GalNAc-HCII reduced HCII levels to 25.04% ± 2.56%, 11.65% ± 2.41%, and 6.50% ± 1.73% with 2, 5, and 10 mg/kg GalNAc-HCII, respectively. The hemostatic ability of hemophilia mice in the GalNAc-HCII-treated group significantly improved, with low thrombus formation time in the carotid artery thrombosis models and short bleeding time in the tail-clipping assays. After repeated administration, the prolonged activated partial thromboplastin time (APTT) was reduced. A 30 mg/kg dose did not cause pathological thrombosis. Our study confirmed that GalNAc-HCII therapy is effective for treating hemophilia mice and can be considered a new option for treating hemophilia patients. |
| Databáze: | OpenAIRE |
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