دورية أكاديمية
أعرض في EDS

Novel endosomolytic compounds enable highly potent delivery of antisense oligonucleotides.

التفاصيل البيبلوغرافية
العنوان: Novel endosomolytic compounds enable highly potent delivery of antisense oligonucleotides.
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
الوصف
تدمد:2399-3642
DOI:10.1038/s42003-022-03132-2