Modeling the Kinetics of Lipid-Nanoparticle- Mediated Delivery of Multiple siRNAs to Evaluate the Effect on Competition for Ago2
| Autor: | R. Matthew Haas, Jing Kang, W. Michael Flanagan, Dipali Ruhela, Nelly A. Kuklin, Samnang Tep, Radu Mihaila, Elena Cherkaev, Jeremy Caldwell, Ananda Card, Timothy R. Shadel, Jie Wei, Brandon Ason, Beverly Galinski, Mark T. Cancilla |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Small interfering RNA Chemistry Endosome Kinetics lcsh:RM1-950 mathematical modeling Future application Computational biology lipid nanoparticles Article combination therapy 03 medical and health sciences 030104 developmental biology 0302 clinical medicine RNA interference lcsh:Therapeutics. Pharmacology Drug development 030220 oncology & carcinogenesis siRNA Drug Discovery MRNA degradation Molecular Medicine competition |
| Zdroj: | Molecular Therapy: Nucleic Acids, Vol 16, Iss, Pp 367-377 (2019) Molecular Therapy. Nucleic Acids |
| ISSN: | 2162-2531 |
| Popis: | Drug combinations can improve the control of diseases involving redundant and highly regulated pathways. Validating a multi-target therapy early in drug development remains difficult. Small interfering RNAs (siRNAs) are routinely used to selectively silence a target of interest. Owing to the ease of design and synthesis, siRNAs hold promise for combination therapies. Combining siRNAs against multiple targets remains an attractive approach to interrogating highly regulated pathways. Currently, questions remain regarding how broadly such an approach can be applied, since siRNAs have been shown to compete with one another for binding to Argonaute2 (Ago2), the protein responsible for initiating siRNA-mediated mRNA degradation. Mathematical modeling, coupled with in vitro and in vivo experiments, led us to conclude that endosomal escape kinetics had the highest impact on Ago2 depletion by competing lipid-nanoparticle (LNP)-formulated siRNAs. This, in turn, affected the level of competition observed between them. A future application of this model would be to optimize delivery of desired siRNA combinations in vitro to attenuate competition and maximize the combined therapeutic effect. Keywords: RNA interference, siRNA, lipid nanoparticles, combination therapy, competition, mathematical modeling |
| Databáze: | OpenAIRE |
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