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Modeling the Kinetics of Lipid-Nanoparticle- Mediated Delivery of Multiple siRNAs to Evaluate the Effect on Competition for Ago2
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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463220/ https://www.ncbi.nlm.nih.gov/pubmed/30991218 http://dx.doi.org/10.1016/j.omtn.2019.03.004 |
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author | Mihaila, Radu Ruhela, Dipali Galinski, Beverly Card, Ananda Cancilla, Mark Shadel, Timothy Kang, Jing Tep, Samnang Wei, Jie Haas, R. Matthew Caldwell, Jeremy Flanagan, W. Michael Kuklin, Nelly Cherkaev, Elena Ason, Brandon |
author_facet | Mihaila, Radu Ruhela, Dipali Galinski, Beverly Card, Ananda Cancilla, Mark Shadel, Timothy Kang, Jing Tep, Samnang Wei, Jie Haas, R. Matthew Caldwell, Jeremy Flanagan, W. Michael Kuklin, Nelly Cherkaev, Elena Ason, Brandon |
author_sort | Mihaila, Radu |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6463220 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-64632202019-04-22 Modeling the Kinetics of Lipid-Nanoparticle- Mediated Delivery of Multiple siRNAs to Evaluate the Effect on Competition for Ago2 Mihaila, Radu Ruhela, Dipali Galinski, Beverly Card, Ananda Cancilla, Mark Shadel, Timothy Kang, Jing Tep, Samnang Wei, Jie Haas, R. Matthew Caldwell, Jeremy Flanagan, W. Michael Kuklin, Nelly Cherkaev, Elena Ason, Brandon Mol Ther Nucleic Acids Article 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. American Society of Gene & Cell Therapy 2019-03-23 /pmc/articles/PMC6463220/ /pubmed/30991218 http://dx.doi.org/10.1016/j.omtn.2019.03.004 Text en © 2019 Merck & Co. Inc. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Mihaila, Radu Ruhela, Dipali Galinski, Beverly Card, Ananda Cancilla, Mark Shadel, Timothy Kang, Jing Tep, Samnang Wei, Jie Haas, R. Matthew Caldwell, Jeremy Flanagan, W. Michael Kuklin, Nelly Cherkaev, Elena Ason, Brandon Modeling the Kinetics of Lipid-Nanoparticle- Mediated Delivery of Multiple siRNAs to Evaluate the Effect on Competition for Ago2 |
title | Modeling the Kinetics of Lipid-Nanoparticle- Mediated Delivery of Multiple siRNAs to Evaluate the Effect on Competition for Ago2 |
title_full | Modeling the Kinetics of Lipid-Nanoparticle- Mediated Delivery of Multiple siRNAs to Evaluate the Effect on Competition for Ago2 |
title_fullStr | Modeling the Kinetics of Lipid-Nanoparticle- Mediated Delivery of Multiple siRNAs to Evaluate the Effect on Competition for Ago2 |
title_full_unstemmed | Modeling the Kinetics of Lipid-Nanoparticle- Mediated Delivery of Multiple siRNAs to Evaluate the Effect on Competition for Ago2 |
title_short | Modeling the Kinetics of Lipid-Nanoparticle- Mediated Delivery of Multiple siRNAs to Evaluate the Effect on Competition for Ago2 |
title_sort | modeling the kinetics of lipid-nanoparticle- mediated delivery of multiple sirnas to evaluate the effect on competition for ago2 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463220/ https://www.ncbi.nlm.nih.gov/pubmed/30991218 http://dx.doi.org/10.1016/j.omtn.2019.03.004 |
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