دورية أكاديمية
Novel endosomolytic compounds enable highly potent delivery of antisense oligonucleotides.
العنوان: | Novel endosomolytic compounds enable highly potent delivery of antisense oligonucleotides. |
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المؤلفون: | Bost JP; Department of Laboratory Medicine, Karolinska Institutet, Huddinge, 14157, Sweden. jeremy.bost@ki.se., Ojansivu M; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, 17177, Sweden., Munson MJ; Advanced Drug Delivery, Pharmaceutical Sciences, Biopharmaceutical R&D, AstraZeneca, Mölndal, 43150, Sweden., Wesén E; Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, 41296, Sweden., Gallud A; Advanced Drug Delivery, Pharmaceutical Sciences, Biopharmaceutical R&D, AstraZeneca, Mölndal, 43150, Sweden.; Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, 41296, Sweden., Gupta D; Department of Laboratory Medicine, Karolinska Institutet, Huddinge, 14157, Sweden., Gustafsson O; Department of Laboratory Medicine, Karolinska Institutet, Huddinge, 14157, Sweden., Saher O; Department of Laboratory Medicine, Karolinska Institutet, Huddinge, 14157, Sweden.; Department of Pharmaceutics and Industrial Pharmacy, Cairo University, Cairo, 11562, Egypt., Rädler J; Department of Laboratory Medicine, Karolinska Institutet, Huddinge, 14157, Sweden., Higgins SG; Department of Materials, Department of Bioengineering, Institute of Biomedical Engineering, Imperial College London, London, SW7 2AZ, United Kingdom., Lehto T; Department of Laboratory Medicine, Karolinska Institutet, Huddinge, 14157, Sweden.; Institute of Technology, University of Tartu, Nooruse 1, Tartu, 50411, Estonia., Holme MN; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, 17177, Sweden., Dahlén A; Discovery Sciences, R&D, AstraZeneca, Gothenburg, 43150, Sweden., Engkvist O; Discovery Sciences, R&D, AstraZeneca, Gothenburg, 43150, Sweden., Strömstedt PE; Discovery Sciences, R&D, AstraZeneca, Gothenburg, 43150, Sweden., Andersson S; Discovery Sciences, R&D, AstraZeneca, Gothenburg, 43150, Sweden., Edvard Smith CI; Department of Laboratory Medicine, Karolinska Institutet, Huddinge, 14157, Sweden., Stevens MM; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, 17177, Sweden.; Department of Materials, Department of Bioengineering, Institute of Biomedical Engineering, Imperial College London, London, SW7 2AZ, United Kingdom., Esbjörner EK; Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, 41296, Sweden., Collén A; Advanced Drug Delivery, Pharmaceutical Sciences, Biopharmaceutical R&D, AstraZeneca, Mölndal, 43150, Sweden.; Projects, Research and Early Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, 43150, Sweden., El Andaloussi S; Department of Laboratory Medicine, Karolinska Institutet, Huddinge, 14157, Sweden. samir.el-andaloussi@ki.se. |
المصدر: | Communications biology [Commun Biol] 2022 Mar 01; Vol. 5 (1), pp. 185. Date of Electronic Publication: 2022 Mar 01. |
نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: Nature Publishing Group UK Country of Publication: England NLM ID: 101719179 Publication Model: Electronic Cited Medium: Internet ISSN: 2399-3642 (Electronic) Linking ISSN: 23993642 NLM ISO Abbreviation: Commun Biol Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: London, United Kingdom : Nature Publishing Group UK, [2018]- |
مواضيع طبية MeSH: | Oligonucleotides*/metabolism , Oligonucleotides, Antisense*/genetics , Oligonucleotides, Antisense*/pharmacology, Endosomes/metabolism ; Intracellular Membranes ; Lysosomes |
مستخلص: | The therapeutic and research potentials of oligonucleotides (ONs) have been hampered in part by their inability to effectively escape endosomal compartments to reach their cytosolic and nuclear targets. Splice-switching ONs (SSOs) can be used with endosomolytic small molecule compounds to increase functional delivery. So far, development of these compounds has been hindered by a lack of high-resolution methods that can correlate SSO trafficking with SSO activity. Here we present in-depth characterization of two novel endosomolytic compounds by using a combination of microscopic and functional assays with high spatiotemporal resolution. This system allows the visualization of SSO trafficking, evaluation of endosomal membrane rupture, and quantitates SSO functional activity on a protein level in the presence of endosomolytic compounds. We confirm that the leakage of SSO into the cytosol occurs in parallel with the physical engorgement of LAMP1-positive late endosomes and lysosomes. We conclude that the new compounds interfere with SSO trafficking to the LAMP1-positive endosomal compartments while inducing endosomal membrane rupture and concurrent ON escape into the cytosol. The efficacy of these compounds advocates their use as novel, potent, and quick-acting transfection reagents for antisense ONs. (© 2022. The Author(s).) |
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معلومات مُعتمدة: | United Kingdom WT_ Wellcome Trust; IRC15-0065 Stiftelsen för Strategisk Forskning (Swedish Foundation for Strategic Research); 098411/Z/12/Z United Kingdom WT_ Wellcome Trust |
المشرفين على المادة: | 0 (Oligonucleotides) 0 (Oligonucleotides, Antisense) |
تواريخ الأحداث: | Date Created: 20220302 Date Completed: 20220404 Latest Revision: 20220405 |
رمز التحديث: | 20231215 |
مُعرف محوري في PubMed: | PMC8888659 |
DOI: | 10.1038/s42003-022-03132-2 |
PMID: | 35233031 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2399-3642 |
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DOI: | 10.1038/s42003-022-03132-2 |