Investigating the pharmacodynamic durability of GalNAc–siRNA conjugates
| العنوان: | Investigating the pharmacodynamic durability of GalNAc–siRNA conjugates |
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| المؤلفون: | Ryan Malone, Christopher S. Theile, Scott Lentini, Muthusamy Jayaraman, Mikyung Yu, Varun Goel, Rubina G. Parmar, Vasant Jadhav, Shigeo Matsuda, Mark K Schlegel, Guo He, Dennis Brown, June Qin, Swati Gupta, Timothy Racie, Svetlana Shulga-Morskaya, Anil V. Nair, Muthiah Manoharan, Jayaprakash K. Nair, Karyn Schmidt, Azar Shahraz, Ivan Zlatev, Christopher R. Brown, Martin Maier |
| المصدر: | Nucleic Acids Research |
| بيانات النشر: | Oxford University Press (OUP), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Small interfering RNA, Acetylgalactosamine, Time Factors, AcademicSubjects/SCI00010, NAR Breakthrough Article, Asialoglycoprotein Receptor, Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, Drug Stability, RNA interference, In vivo, Genetics, Animals, Humans, Prealbumin, Gene silencing, Gene Silencing, RNA, Small Interfering, 030304 developmental biology, Drug Carriers, 0303 health sciences, Gene knockdown, Biological Transport, Biological activity, Hydrogen-Ion Concentration, Argonaute, Cell biology, Mice, Inbred C57BL, Liver, 030220 oncology & carcinogenesis, Argonaute Proteins, Hepatocytes, Nanoparticles, Female, Glycoconjugates, Intracellular |
| الوصف: | One hallmark of trivalent N-acetylgalactosamine (GalNAc)-conjugated siRNAs is the remarkable durability of silencing that can persist for months in preclinical species and humans. Here, we investigated the underlying biology supporting this extended duration of pharmacological activity. We found that siRNA accumulation and stability in acidic intracellular compartments is critical for long-term activity. We show that functional siRNA can be liberated from these compartments and loaded into newly generated Argonaute 2 protein complexes weeks after dosing, enabling continuous RNAi activity over time. Identical siRNAs delivered in lipid nanoparticles or as GalNAc conjugates were dose-adjusted to achieve similar knockdown, but only GalNAc–siRNAs supported an extended duration of activity, illustrating the importance of receptor-mediated siRNA trafficking in the process. Taken together, we provide several lines of evidence that acidic intracellular compartments serve as a long-term depot for GalNAc–siRNA conjugates and are the major contributor to the extended duration of activity observed in vivo. |
| تدمد: | 1362-4962 0305-1048 |
| DOI: | 10.1093/nar/gkaa670 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::36fdc48fda489ac5921e9de415b9c04b https://doi.org/10.1093/nar/gkaa670 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....36fdc48fda489ac5921e9de415b9c04b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 13624962 03051048 |
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| DOI: | 10.1093/nar/gkaa670 |