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siRNA-mediated reduction of a circulating protein in swine using lipid nanoparticles.
Cau, Massimo F; Ferraresso, Francesca; Seadler, Monica; Badior, Katherine; Zhang, Youjie; Ketelboeter, Laura M; Rodriguez, Geoffrey G; Chen, Taylor; Ferraresso, Matteo; Wietrzny, Amanda; Robertson, Madelaine; Haugen, Amber; Cullis, Pieter R; de Moya, Marc; Dyer, Mitchell; Kastrup, Christian J.
Afiliación
  • Cau MF; Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
  • Ferraresso F; School of Biomedical Engineering, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
  • Seadler M; Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
  • Badior K; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
  • Zhang Y; Versiti Blood Research Institute, Milwaukee, WI 53226, USA.
  • Ketelboeter LM; Versiti Blood Research Institute, Milwaukee, WI 53226, USA.
  • Rodriguez GG; Department of Surgery, Division of Trauma and Acute Care Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
  • Chen T; Versiti Blood Research Institute, Milwaukee, WI 53226, USA.
  • Ferraresso M; Versiti Blood Research Institute, Milwaukee, WI 53226, USA.
  • Wietrzny A; Versiti Blood Research Institute, Milwaukee, WI 53226, USA.
  • Robertson M; Versiti Blood Research Institute, Milwaukee, WI 53226, USA.
  • Haugen A; Versiti Blood Research Institute, Milwaukee, WI 53226, USA.
  • Cullis PR; Versiti Blood Research Institute, Milwaukee, WI 53226, USA.
  • de Moya M; Versiti Blood Research Institute, Milwaukee, WI 53226, USA.
  • Dyer M; Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
  • Kastrup CJ; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
Mol Ther Methods Clin Dev ; 32(2): 101258, 2024 Jun 13.
Article en En | MEDLINE | ID: mdl-38779336
ABSTRACT
Genetic manipulation of animal models is a fundamental research tool in biology and medicine but is challenging in large animals. In rodents, models can be readily developed by knocking out genes in embryonic stem cells or by knocking down genes through in vivo delivery of nucleic acids. Swine are a preferred animal model for studying the cardiovascular and immune systems, but there are limited strategies for genetic manipulation. Lipid nanoparticles (LNPs) efficiently deliver small interfering RNA (siRNA) to knock down circulating proteins, but swine are sensitive to LNP-induced complement activation-related pseudoallergy (CARPA). We hypothesized that appropriately administering optimized siRNA-LNPs could knock down circulating levels of plasminogen, a blood protein synthesized in the liver. siRNA-LNPs against plasminogen (siPLG) reduced plasma plasminogen protein and hepatic plasminogen mRNA levels to below 5% of baseline values. Functional assays showed that reducing plasminogen levels modulated systemic blood coagulation. Clinical signs of CARPA were not observed, and occasional mild and transient hepatotoxicity was present in siPLG-treated animals at 5 h post-infusion, which returned to baseline by 7 days. These findings advance siRNA-LNPs in swine models, enabling genetic engineering of blood and hepatic proteins, which can likely expand to proteins in other tissues in the future.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Mol Ther Methods Clin Dev Año: 2024 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Mol Ther Methods Clin Dev Año: 2024 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos