| Literature DB >> 25625614 |
Zhu Chen1, Bin Luo2, Tian-Quan Cai3, Anil Thankappan4, Yiming Xu1, Weizhen Wu1, Jillian DiMuzio4, Traci Lifsted2, Marty DiPietro4, Jyoti Disa4, Bruce Ng4, Karen Leander4, Seth Clark5, Lizbeth Hoos3, Yuchen Zhou3, Nina Jochnowitz3, Christine Jachec1, Peter Szczerba6, Marian E Gindy7, Walter Strapps4, Laura Sepp-Lorenzino4, Dietmar A Seiffert1, Laura Lubbers2, Marija Tadin-Strapps4.
Abstract
The present study aimed at establishing feasibility of delivering short interfering RNA (siRNA) to target the coagulation cascade in rat and rabbit, two commonly used species for studying thrombosis and hemostasis. siRNAs that produced over 90% mRNA knockdown of rat plasma prekallikrein and rabbit Factor X (FX) were identified from in vitro screens. An ionizable amino lipid based lipid nanoparticle (LNP) formulation for siRNA in vivo delivery was characterized as tolerable and exerting no appreciable effect on coagulability at day 7 postdosing in both species. Both prekallikrein siRNA-LNP and FX siRNA-LNP resulted in dose-dependent and selective knockdown of target gene mRNA in the liver with maximum reduction of over 90% on day 7 following a single dose of siRNA-LNP. Knockdown of plasma prekallikrein was associated with modest clot weight reduction in the rat arteriovenous shunt thrombosis model and no increase in the cuticle bleeding time. Knockdown of FX in the rabbit was accompanied with prolongation in ex vivo clotting times. Results fit the expectations with both targets and demonstrate for the first time, the feasibility of targeting coagulation factors in rat, and, more broadly, targeting a gene of interest in rabbit, via systemic delivery of ionizable LNP formulated siRNA.Entities:
Year: 2015 PMID： 25625614 PMCID： PMC4345307 DOI： 10.1038/mtna.2014.75
Source DB: PubMed Journal: Mol Ther Nucleic Acids ISSN： 2162-2531 Impact factor: 10.183