Titrating haemophilia B phenotypes using siRNA strategy: evidence that antithrombotic activity is separated from bleeding liability

التفاصيل البيبلوغرافية
العنوان: Titrating haemophilia B phenotypes using siRNA strategy: evidence that antithrombotic activity is separated from bleeding liability
المؤلفون: Lizbeth M. Hoos, Laura Sepp-Lorenzino, Walter Strapps, John Levorse, Dietmar Seiffert, Karen R. Leander, Marti DiPietro, Yuchen Zhou, Anil Thankappan, Weizhen Wu, Tian-Quan Cai, Zuo Zhang, Zhu Chen, Yiming Xu, Marija Tadin-Strapps, Myung K. Shin, Patrick Andre, Joseph M. Metzger, Kunal Desai, KehDih Lai, Nina Jochnowitz, Ross Bentley
المصدر: Thrombosis and haemostasis. 113(6)
سنة النشر: 2014
مصطلحات موضوعية: Male, medicine.medical_specialty, Small interfering RNA, Time Factors, Genotype, Haemophilia A, Hemorrhage, 030204 cardiovascular system & hematology, Pharmacology, Transfection, Ferric Compounds, Hemophilia B, Cell Line, Factor IX, Rats, Sprague-Dawley, 03 medical and health sciences, 0302 clinical medicine, Chlorides, Bleeding time, Antithrombotic, medicine, Gene silencing, Animals, Haemophilia B, RNA, Messenger, RNA, Small Interfering, Gene knockdown, Hemostasis, medicine.diagnostic_test, business.industry, Thrombosis, Hematology, medicine.disease, Surgery, Rats, Disease Models, Animal, Phenotype, RNAi Therapeutics, Gene Expression Regulation, Liver, 030220 oncology & carcinogenesis, RNA Interference, Rats, Transgenic, business, medicine.drug
الوصف: SummaryHaemophilia A and B are characterised by a life-long bleeding predisposition, and several lines of evidence suggest that risks of atherothrombotic events may also be reduced. Establishing a direct correlation between coagulation factor levels, thrombotic risks and bleeding propensity has long been hampered by an inability to selectively and specifically inhibit coagulation factor levels. Here, the exquisite selectivity of gene silencing combined with a gene knockout (KO) approach was used to define the relative contribution of factor IX (fIX) to thrombosis and primary haemostasis in the rat. Using a lipid nanoparticle (LNP) formulation, we successfully delivered fIX siRNAs to the liver by intravenous administration. The knockdown (KD) of target gene mRNA was achieved rapidly (within 24 hour post-siRNA dosing), sustained (maintained for at least 7 days post dosing) and not associated with changes in mRNA expression levels of other coagulation factors. We found that intermediate levels of liver fIX mRNA silencing (60–95 %) translating into a 50–99 % reduction of plasma fIX activity provided protection from thrombosis without prolonging the cuticle bleeding time. Over 99 % inhibition of fIX activity was required to observe increase in bleeding, a phenotype confirmed in fIX KO rats. These data provide substantial evidence of a participation of fIX in the mechanisms regulating thrombosis prior to those regulating primary haemostasis, therefore highlighting the potential of fIX as a therapeutic target. In addition, hepatic mRNA silencing using LNP-encapsulated siRNAs may represent a promising novel approach for the chronic treatment and prevention of coagulation-dependent thrombotic disorders in humans.
تدمد: 2567-689X
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c451ee47e663a79cf3f2011d6a5ea178
https://pubmed.ncbi.nlm.nih.gov/25790442
رقم الأكسشن: edsair.doi.dedup.....c451ee47e663a79cf3f2011d6a5ea178
قاعدة البيانات: OpenAIRE