Erica Bäckström, Alessandro Bonetti, Per Johnsson, Stefan Öhlin, Anders Dahlén, Patrik Andersson, Shalini Andersson, Peter Gennemark
{"title":"Tissue pharmacokinetics of antisense oligonucleotides","authors":"Erica Bäckström, Alessandro Bonetti, Per Johnsson, Stefan Öhlin, Anders Dahlén, Patrik Andersson, Shalini Andersson, Peter Gennemark","doi":"10.1016/j.omtn.2024.102133","DOIUrl":null,"url":null,"abstract":"<p>Pharmacokinetics of antisense oligonucleotides (ASO) is characterized by rapid distribution from plasma to tissue and slow terminal plasma elimination driven by re-distribution from tissue. Quantitative understanding of tissue pharmacokinetics and RNA knockdown for various ASO chemistries, conjugations and administration routes is critical for successful drug discovery. Here, we report concentration-time and RNA knockdown profiles for a gapmer ASO with locked nucleic acid ribose chemistry in mouse liver, kidney, heart, and lung after subcutaneous and intratracheal administration. Additionally, the same ASO with liver targeting conjugation (galactosamine-<em>N</em>-acetyl) is evaluated for subcutaneous administration. Data indicate that exposure and knockdown differ between tissues, and strongly depends on administration route and conjugation. In a second study, we show that tissue pharmacokinetics is similar between the three different ribose chemistries locked nucleic acid, constrained ethyl and 2′-<em>O</em>-methoxyethyl, both after subcutaneous and intratracheal administration. Further, we show that the half-life in mouse liver may vary with ASO sequence. Finally, we report less than dose-proportional increase in liver concentration in the dose range 3 to 30 μmol/kg. Overall, our studies contribute pivotal data to support design and interpretation of ASO <em>in vivo</em> studies, thereby increasing the probability of delivering novel ASO therapies to patients.</p>","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":null,"pages":null},"PeriodicalIF":6.5000,"publicationDate":"2024-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Therapy. Nucleic Acids","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.omtn.2024.102133","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
Abstract
Pharmacokinetics of antisense oligonucleotides (ASO) is characterized by rapid distribution from plasma to tissue and slow terminal plasma elimination driven by re-distribution from tissue. Quantitative understanding of tissue pharmacokinetics and RNA knockdown for various ASO chemistries, conjugations and administration routes is critical for successful drug discovery. Here, we report concentration-time and RNA knockdown profiles for a gapmer ASO with locked nucleic acid ribose chemistry in mouse liver, kidney, heart, and lung after subcutaneous and intratracheal administration. Additionally, the same ASO with liver targeting conjugation (galactosamine-N-acetyl) is evaluated for subcutaneous administration. Data indicate that exposure and knockdown differ between tissues, and strongly depends on administration route and conjugation. In a second study, we show that tissue pharmacokinetics is similar between the three different ribose chemistries locked nucleic acid, constrained ethyl and 2′-O-methoxyethyl, both after subcutaneous and intratracheal administration. Further, we show that the half-life in mouse liver may vary with ASO sequence. Finally, we report less than dose-proportional increase in liver concentration in the dose range 3 to 30 μmol/kg. Overall, our studies contribute pivotal data to support design and interpretation of ASO in vivo studies, thereby increasing the probability of delivering novel ASO therapies to patients.
期刊介绍:
Molecular Therapy Nucleic Acids is an international, open-access journal that publishes high-quality research in nucleic-acid-based therapeutics to treat and correct genetic and acquired diseases. It is the official journal of the American Society of Gene & Cell Therapy and is built upon the success of Molecular Therapy. The journal focuses on gene- and oligonucleotide-based therapies and publishes peer-reviewed research, reviews, and commentaries. Its impact factor for 2022 is 8.8. The subject areas covered include the development of therapeutics based on nucleic acids and their derivatives, vector development for RNA-based therapeutics delivery, utilization of gene-modifying agents like Zn finger nucleases and triplex-forming oligonucleotides, pre-clinical target validation, safety and efficacy studies, and clinical trials.