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Targeting Translation Termination Machinery with Antisense Oligonucleotides for Diseases Caused by Nonsense Mutations

Efforts to develop treatments for diseases caused by nonsense mutations have focused on identification of small molecules that promote translational read-through of messenger RNAs (mRNAs) harboring nonsense stop codons to produce full-length proteins. However, to date, no small molecule read-through...

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Autores principales: Huang, Lulu, Aghajan, Mariam, Quesenberry, Tianna, Low, Audrey, Murray, Susan F., Monia, Brett P., Guo, Shuling
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Mary Ann Liebert, Inc., publishers 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686700/
https://www.ncbi.nlm.nih.gov/pubmed/31070517
http://dx.doi.org/10.1089/nat.2019.0779
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author Huang, Lulu
Aghajan, Mariam
Quesenberry, Tianna
Low, Audrey
Murray, Susan F.
Monia, Brett P.
Guo, Shuling
author_facet Huang, Lulu
Aghajan, Mariam
Quesenberry, Tianna
Low, Audrey
Murray, Susan F.
Monia, Brett P.
Guo, Shuling
author_sort Huang, Lulu
collection PubMed
description Efforts to develop treatments for diseases caused by nonsense mutations have focused on identification of small molecules that promote translational read-through of messenger RNAs (mRNAs) harboring nonsense stop codons to produce full-length proteins. However, to date, no small molecule read-through drug has received FDA approval, probably because of a lack of balance between efficacy and safety. Depletion of translation termination factors eukaryotic release factor (eRF) 1 and eRF3a in cells was shown to promote translational read-through of a luciferase reporter gene harboring a nonsense mutation. In this study, we identified antisense oligonucleotides (ASOs) targeting translation termination factors and determined if ASO-mediated depletion of these factors could be a potentially effective and safe therapeutic approach for diseases caused by nonsense mutations. We found that ASO-mediated reduction of either eRF1 or eRF3a to 30%–40% of normal levels in the mouse liver is well tolerated. Hemophilia mice that express a mutant allele of human coagulation factor IX (FIX) containing nonsense mutation R338X were treated with eRF1- or eRF3a-ASO. We found that although eRF1- or eRF3a-ASO alone only elicited a moderate read-through effect on hFIX-R338X mRNA, both worked in synergy with geneticin, a small molecule read-through drug, demonstrating significantly increased production of functional full-length hFIX protein to levels that would rescue disease phenotypes in these mice. Overall our results indicate that modulating the translation termination pathway in the liver by ASOs may provide a novel approach to improving the efficacy of small molecule read-through drugs to treat human genetic diseases caused by nonsense mutations.
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spelling pubmed-66867002019-08-12 Targeting Translation Termination Machinery with Antisense Oligonucleotides for Diseases Caused by Nonsense Mutations Huang, Lulu Aghajan, Mariam Quesenberry, Tianna Low, Audrey Murray, Susan F. Monia, Brett P. Guo, Shuling Nucleic Acid Ther Original Articles Efforts to develop treatments for diseases caused by nonsense mutations have focused on identification of small molecules that promote translational read-through of messenger RNAs (mRNAs) harboring nonsense stop codons to produce full-length proteins. However, to date, no small molecule read-through drug has received FDA approval, probably because of a lack of balance between efficacy and safety. Depletion of translation termination factors eukaryotic release factor (eRF) 1 and eRF3a in cells was shown to promote translational read-through of a luciferase reporter gene harboring a nonsense mutation. In this study, we identified antisense oligonucleotides (ASOs) targeting translation termination factors and determined if ASO-mediated depletion of these factors could be a potentially effective and safe therapeutic approach for diseases caused by nonsense mutations. We found that ASO-mediated reduction of either eRF1 or eRF3a to 30%–40% of normal levels in the mouse liver is well tolerated. Hemophilia mice that express a mutant allele of human coagulation factor IX (FIX) containing nonsense mutation R338X were treated with eRF1- or eRF3a-ASO. We found that although eRF1- or eRF3a-ASO alone only elicited a moderate read-through effect on hFIX-R338X mRNA, both worked in synergy with geneticin, a small molecule read-through drug, demonstrating significantly increased production of functional full-length hFIX protein to levels that would rescue disease phenotypes in these mice. Overall our results indicate that modulating the translation termination pathway in the liver by ASOs may provide a novel approach to improving the efficacy of small molecule read-through drugs to treat human genetic diseases caused by nonsense mutations. Mary Ann Liebert, Inc., publishers 2019-08-01 2019-08-06 /pmc/articles/PMC6686700/ /pubmed/31070517 http://dx.doi.org/10.1089/nat.2019.0779 Text en © Lulu Huang et al. 2019; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Huang, Lulu
Aghajan, Mariam
Quesenberry, Tianna
Low, Audrey
Murray, Susan F.
Monia, Brett P.
Guo, Shuling
Targeting Translation Termination Machinery with Antisense Oligonucleotides for Diseases Caused by Nonsense Mutations
title Targeting Translation Termination Machinery with Antisense Oligonucleotides for Diseases Caused by Nonsense Mutations
title_full Targeting Translation Termination Machinery with Antisense Oligonucleotides for Diseases Caused by Nonsense Mutations
title_fullStr Targeting Translation Termination Machinery with Antisense Oligonucleotides for Diseases Caused by Nonsense Mutations
title_full_unstemmed Targeting Translation Termination Machinery with Antisense Oligonucleotides for Diseases Caused by Nonsense Mutations
title_short Targeting Translation Termination Machinery with Antisense Oligonucleotides for Diseases Caused by Nonsense Mutations
title_sort targeting translation termination machinery with antisense oligonucleotides for diseases caused by nonsense mutations
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686700/
https://www.ncbi.nlm.nih.gov/pubmed/31070517
http://dx.doi.org/10.1089/nat.2019.0779
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