RNAi targeting heparin cofactor II promotes hemostasis in hemophilia A
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 interferen...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-06-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253121000937 |
| _version_ | 1818864912454123520 |
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| author | Wen-yi Lin Ruiqi Zhu Zhen Zhang Xuan Lu Huafang Wang Wenjuan He Yu Hu Liang Tang |
| author_facet | Wen-yi Lin Ruiqi Zhu Zhen Zhang Xuan Lu Huafang Wang Wenjuan He Yu Hu Liang Tang |
| author_sort | Wen-yi Lin |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T10:39:12Z |
| format | Article |
| id | doaj.art-0ee240cb6122443a861385593a1e3bbe |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-19T10:39:12Z |
| publishDate | 2021-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-0ee240cb6122443a861385593a1e3bbe2022-12-21T20:25:30ZengElsevierMolecular Therapy: Nucleic Acids2162-25312021-06-0124658668RNAi targeting heparin cofactor II promotes hemostasis in hemophilia AWen-yi Lin0Ruiqi Zhu1Zhen Zhang2Xuan Lu3Huafang Wang4Wenjuan He5Yu Hu6Liang Tang7Institute of Hematology, Union Hospital Affiliated Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaInstitute of Hematology, Union Hospital Affiliated Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaInstitute of Hematology, Union Hospital Affiliated Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaInstitute of Hematology, Union Hospital Affiliated Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaInstitute of Hematology, Union Hospital Affiliated Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaInstitute of Hematology, Union Hospital Affiliated Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaInstitute of Hematology, Union Hospital Affiliated Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Corresponding author: Yu Hu, Institute of Hematology, Union Hospital Affiliated Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Dadao, Wuhan 430022, China.Institute of Hematology, Union Hospital Affiliated Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Corresponding author: Liang Tang, Institute of Hematology, Union Hospital Affiliated Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Dadao, Wuhan 430022, China.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.http://www.sciencedirect.com/science/article/pii/S2162253121000937hemostasishemophiliaRNA interferenceheparin cofactor IIthrombin |
| spellingShingle | Wen-yi Lin Ruiqi Zhu Zhen Zhang Xuan Lu Huafang Wang Wenjuan He Yu Hu Liang Tang RNAi targeting heparin cofactor II promotes hemostasis in hemophilia A Molecular Therapy: Nucleic Acids hemostasis hemophilia RNA interference heparin cofactor II thrombin |
| title | RNAi targeting heparin cofactor II promotes hemostasis in hemophilia A |
| title_full | RNAi targeting heparin cofactor II promotes hemostasis in hemophilia A |
| title_fullStr | RNAi targeting heparin cofactor II promotes hemostasis in hemophilia A |
| title_full_unstemmed | RNAi targeting heparin cofactor II promotes hemostasis in hemophilia A |
| title_short | RNAi targeting heparin cofactor II promotes hemostasis in hemophilia A |
| title_sort | rnai targeting heparin cofactor ii promotes hemostasis in hemophilia a |
| topic | hemostasis hemophilia RNA interference heparin cofactor II thrombin |
| url | http://www.sciencedirect.com/science/article/pii/S2162253121000937 |
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