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Proof-of-concept Studies for siRNA-mediated Gene Silencing for Coagulation Factors in Rat and Rabbit

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 F...

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Autores principales: Chen, Zhu, Luo, Bin, Cai, Tian-Quan, Thankappan, Anil, Xu, Yiming, Wu, Weizhen, DiMuzio, Jillian, Lifsted, Traci, DiPietro, Marty, Disa, Jyoti, Ng, Bruce, Leander, Karen, Clark, Seth, Hoos, Lizbeth, Zhou, Yuchen, Jochnowitz, Nina, Jachec, Christine, Szczerba, Peter, Gindy, Marian E., Strapps, Walter, Sepp-Lorenzino, Laura, Seiffert, Dietmar A., Lubbers, Laura, Tadin-Strapps, Marija
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4345307/
https://www.ncbi.nlm.nih.gov/pubmed/25625614
http://dx.doi.org/10.1038/mtna.2014.75
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author Chen, Zhu
Luo, Bin
Cai, Tian-Quan
Thankappan, Anil
Xu, Yiming
Wu, Weizhen
DiMuzio, Jillian
Lifsted, Traci
DiPietro, Marty
Disa, Jyoti
Ng, Bruce
Leander, Karen
Clark, Seth
Hoos, Lizbeth
Zhou, Yuchen
Jochnowitz, Nina
Jachec, Christine
Szczerba, Peter
Gindy, Marian E.
Strapps, Walter
Sepp-Lorenzino, Laura
Seiffert, Dietmar A.
Lubbers, Laura
Tadin-Strapps, Marija
author_facet Chen, Zhu
Luo, Bin
Cai, Tian-Quan
Thankappan, Anil
Xu, Yiming
Wu, Weizhen
DiMuzio, Jillian
Lifsted, Traci
DiPietro, Marty
Disa, Jyoti
Ng, Bruce
Leander, Karen
Clark, Seth
Hoos, Lizbeth
Zhou, Yuchen
Jochnowitz, Nina
Jachec, Christine
Szczerba, Peter
Gindy, Marian E.
Strapps, Walter
Sepp-Lorenzino, Laura
Seiffert, Dietmar A.
Lubbers, Laura
Tadin-Strapps, Marija
author_sort Chen, Zhu
collection PubMed
description 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.
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spelling pubmed-43453072015-03-09 Proof-of-concept Studies for siRNA-mediated Gene Silencing for Coagulation Factors in Rat and Rabbit Chen, Zhu Luo, Bin Cai, Tian-Quan Thankappan, Anil Xu, Yiming Wu, Weizhen DiMuzio, Jillian Lifsted, Traci DiPietro, Marty Disa, Jyoti Ng, Bruce Leander, Karen Clark, Seth Hoos, Lizbeth Zhou, Yuchen Jochnowitz, Nina Jachec, Christine Szczerba, Peter Gindy, Marian E. Strapps, Walter Sepp-Lorenzino, Laura Seiffert, Dietmar A. Lubbers, Laura Tadin-Strapps, Marija Mol Ther Nucleic Acids Original Article 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. Nature Publishing Group 2015-01 2015-01-27 /pmc/articles/PMC4345307/ /pubmed/25625614 http://dx.doi.org/10.1038/mtna.2014.75 Text en Copyright © 2015 American Society of Gene & Cell Therapy
spellingShingle Original Article
Chen, Zhu
Luo, Bin
Cai, Tian-Quan
Thankappan, Anil
Xu, Yiming
Wu, Weizhen
DiMuzio, Jillian
Lifsted, Traci
DiPietro, Marty
Disa, Jyoti
Ng, Bruce
Leander, Karen
Clark, Seth
Hoos, Lizbeth
Zhou, Yuchen
Jochnowitz, Nina
Jachec, Christine
Szczerba, Peter
Gindy, Marian E.
Strapps, Walter
Sepp-Lorenzino, Laura
Seiffert, Dietmar A.
Lubbers, Laura
Tadin-Strapps, Marija
Proof-of-concept Studies for siRNA-mediated Gene Silencing for Coagulation Factors in Rat and Rabbit
title Proof-of-concept Studies for siRNA-mediated Gene Silencing for Coagulation Factors in Rat and Rabbit
title_full Proof-of-concept Studies for siRNA-mediated Gene Silencing for Coagulation Factors in Rat and Rabbit
title_fullStr Proof-of-concept Studies for siRNA-mediated Gene Silencing for Coagulation Factors in Rat and Rabbit
title_full_unstemmed Proof-of-concept Studies for siRNA-mediated Gene Silencing for Coagulation Factors in Rat and Rabbit
title_short Proof-of-concept Studies for siRNA-mediated Gene Silencing for Coagulation Factors in Rat and Rabbit
title_sort proof-of-concept studies for sirna-mediated gene silencing for coagulation factors in rat and rabbit
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4345307/
https://www.ncbi.nlm.nih.gov/pubmed/25625614
http://dx.doi.org/10.1038/mtna.2014.75
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