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Target mRNA inhibition by oligonucleotide drugs in man

Oligonucleotide delivery in vivo is commonly seen as the principal hurdle to the successful development of oligonucleotide drugs. In an analysis of 26 oligonucleotide drugs recently evaluated in late-stage clinical trials we found that to date at least half have demonstrated suppression of the targe...

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Detalles Bibliográficos
Autores principales: Lightfoot, Helen L., Hall, Jonathan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3510500/
https://www.ncbi.nlm.nih.gov/pubmed/22989709
http://dx.doi.org/10.1093/nar/gks861
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author Lightfoot, Helen L.
Hall, Jonathan
author_facet Lightfoot, Helen L.
Hall, Jonathan
author_sort Lightfoot, Helen L.
collection PubMed
description Oligonucleotide delivery in vivo is commonly seen as the principal hurdle to the successful development of oligonucleotide drugs. In an analysis of 26 oligonucleotide drugs recently evaluated in late-stage clinical trials we found that to date at least half have demonstrated suppression of the target mRNA and/or protein levels in the relevant cell types in man, including those present in liver, muscle, bone marrow, lung, blood and solid tumors. Overall, this strongly implies that the drugs are being delivered to the appropriate disease tissues. Strikingly we also found that the majority of the drug targets of the oligonucleotides lie outside of the drugable genome and represent new mechanisms of action not previously investigated in a clinical setting. Despite the high risk of failure of novel mechanisms of action in the clinic, a subset of the targets has been validated by the drugs. While not wishing to downplay the technical challenges of oligonucleotide delivery in vivo, here we demonstrate that target selection and validation are of equal importance for the success of this field.
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spelling pubmed-35105002012-11-30 Target mRNA inhibition by oligonucleotide drugs in man Lightfoot, Helen L. Hall, Jonathan Nucleic Acids Res Survey and Summary Oligonucleotide delivery in vivo is commonly seen as the principal hurdle to the successful development of oligonucleotide drugs. In an analysis of 26 oligonucleotide drugs recently evaluated in late-stage clinical trials we found that to date at least half have demonstrated suppression of the target mRNA and/or protein levels in the relevant cell types in man, including those present in liver, muscle, bone marrow, lung, blood and solid tumors. Overall, this strongly implies that the drugs are being delivered to the appropriate disease tissues. Strikingly we also found that the majority of the drug targets of the oligonucleotides lie outside of the drugable genome and represent new mechanisms of action not previously investigated in a clinical setting. Despite the high risk of failure of novel mechanisms of action in the clinic, a subset of the targets has been validated by the drugs. While not wishing to downplay the technical challenges of oligonucleotide delivery in vivo, here we demonstrate that target selection and validation are of equal importance for the success of this field. Oxford University Press 2012-11 2012-09-18 /pmc/articles/PMC3510500/ /pubmed/22989709 http://dx.doi.org/10.1093/nar/gks861 Text en © The Author(s) 2012. Published by Oxford University Press. http://creativecommons.org/licenses/by/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Survey and Summary
Lightfoot, Helen L.
Hall, Jonathan
Target mRNA inhibition by oligonucleotide drugs in man
title Target mRNA inhibition by oligonucleotide drugs in man
title_full Target mRNA inhibition by oligonucleotide drugs in man
title_fullStr Target mRNA inhibition by oligonucleotide drugs in man
title_full_unstemmed Target mRNA inhibition by oligonucleotide drugs in man
title_short Target mRNA inhibition by oligonucleotide drugs in man
title_sort target mrna inhibition by oligonucleotide drugs in man
topic Survey and Summary
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3510500/
https://www.ncbi.nlm.nih.gov/pubmed/22989709
http://dx.doi.org/10.1093/nar/gks861
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