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Comparison of DLin-MC3-DMA and ALC-0315 for siRNA Delivery to Hepatocytes and Hepatic Stellate Cells.
Ferraresso, Francesca; Strilchuk, Amy W; Juang, Lih Jiin; Poole, Lauren G; Luyendyk, James P; Kastrup, Christian J.
  • Ferraresso F; Michael Smith Laboratories and Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
  • Strilchuk AW; Michael Smith Laboratories and Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
  • Juang LJ; Michael Smith Laboratories and Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
  • Poole LG; Department of Pathobiology and Diagnostic Investigation, Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48823, United States.
  • Luyendyk JP; Department of Pathobiology and Diagnostic Investigation, Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48823, United States.
  • Kastrup CJ; Michael Smith Laboratories and Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
Mol Pharm ; 19(7): 2175-2182, 2022 07 04.
Article in English | MEDLINE | ID: covidwho-1873399
ABSTRACT
Ionizable cationic lipids are essential for efficient in vivo delivery of RNA by lipid nanoparticles (LNPs). DLin-MC3-DMA (MC3), ALC-0315, and SM-102 are the only ionizable cationic lipids currently clinically approved for RNA therapies. ALC-0315 and SM-102 are structurally similar lipids used in SARS-CoV-2 mRNA vaccines, while MC3 is used in siRNA therapy to knock down transthyretin in hepatocytes. Hepatocytes and hepatic stellate cells (HSCs) are particularly attractive targets for RNA therapy because they synthesize many plasma proteins, including those that influence blood coagulation. While LNPs preferentially accumulate in the liver, evaluating the ability of different ionizable cationic lipids to deliver RNA cargo into distinct cell populations is important for designing RNA-LNP therapies with minimal hepatotoxicity. Here, we directly compared LNPs containing either ALC-0315 or MC3 to knock-down coagulation factor VII (FVII) in hepatocytes and ADAMTS13 in HSCs. At a dose of 1 mg/kg siRNA in mice, LNPs with ALC-0315 achieved a 2- and 10-fold greater knockdown of FVII and ADAMTS13, respectively, compared to LNPs with MC3. At a high dose (5 mg/kg), ALC-0315 LNPs increased markers of liver toxicity (ALT and bile acids), while the same dose of MC3 LNPs did not. These results demonstrate that ALC-0315 LNPs achieves potent siRNA-mediated knockdown of target proteins in hepatocytes and HSCs, in mice, though markers of liver toxicity can be observed after a high dose. This study provides an initial comparison that may inform the development of ionizable cationic LNP therapeutics with maximal efficacy and limited toxicity.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Nanoparticles / COVID-19 Type of study: Experimental Studies / Prognostic study Topics: Vaccines Limits: Animals Language: English Journal: Mol Pharm Journal subject: Molecular Biology / Pharmacy / Pharmacology Year: 2022 Document Type: Article Affiliation country: Acs.molpharmaceut.2c00033

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Nanoparticles / COVID-19 Type of study: Experimental Studies / Prognostic study Topics: Vaccines Limits: Animals Language: English Journal: Mol Pharm Journal subject: Molecular Biology / Pharmacy / Pharmacology Year: 2022 Document Type: Article Affiliation country: Acs.molpharmaceut.2c00033