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Preclinical Studies on Intestinal Administration of Antisense Oligonucleotides as a Model for Oral Delivery for Treatment of Duchenne Muscular Dystrophy

Antisense oligonucleotides (AONs) used to reframe dystrophin mRNA transcripts for Duchenne muscular dystrophy (DMD) patients are tested in clinical trials. Here, AONs are administered subcutaneously and intravenously, while the less invasive oral route would be preferred. Oral delivery of encapsulat...

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Autores principales: van Putten, Maaike, Young, Courtney, van den Berg, Sjoerd, Pronk, Amanda, Hulsker, Margriet, Karnaoukh, Tatyana G, Vermue, Rick, van Dijk, Ko Willems, de Kimpe, Sjef, Aartsma-Rus, Annemieke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459548/
https://www.ncbi.nlm.nih.gov/pubmed/25405468
http://dx.doi.org/10.1038/mtna.2014.62
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author van Putten, Maaike
Young, Courtney
van den Berg, Sjoerd
Pronk, Amanda
Hulsker, Margriet
Karnaoukh, Tatyana G
Vermue, Rick
van Dijk, Ko Willems
de Kimpe, Sjef
Aartsma-Rus, Annemieke
author_facet van Putten, Maaike
Young, Courtney
van den Berg, Sjoerd
Pronk, Amanda
Hulsker, Margriet
Karnaoukh, Tatyana G
Vermue, Rick
van Dijk, Ko Willems
de Kimpe, Sjef
Aartsma-Rus, Annemieke
author_sort van Putten, Maaike
collection PubMed
description Antisense oligonucleotides (AONs) used to reframe dystrophin mRNA transcripts for Duchenne muscular dystrophy (DMD) patients are tested in clinical trials. Here, AONs are administered subcutaneously and intravenously, while the less invasive oral route would be preferred. Oral delivery of encapsulated AONs supplemented with a permeation enhancer, sodium caprate, has been successfully used to target tumor necrosis factor (TNF)-α expression in liver. To test the feasibility of orally delivered AONs for DMD, we applied 2′-O-methyl phosphorothioate AONs (with or without sodium caprate supplementation) directly to the intestine of mdx mice and compared pharmacokinetics and -dynamics with intravenous, intraperitoneal, and subcutaneous delivery. Intestinally infused AONs were taken up, but resulted in lower plasma levels compared to other delivery routes, although bioavailability could be largely improved by supplementation of sodium caprate. After intestinal infusion, AON levels in all tissues were lower than for other administration routes, as were the ratios of target versus nontarget organ levels, except for diaphragm and heart where comparable levels and ratios were observed. For each administration route, low levels of exon skipping in triceps was observed 3 hours post-AON administration. These data suggest that oral administration of naked 2′-O-methyl phosphorothioate AONs may be feasible, but only when high AON concentrations are used in combination with sodium caprate.
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spelling pubmed-44595482015-06-22 Preclinical Studies on Intestinal Administration of Antisense Oligonucleotides as a Model for Oral Delivery for Treatment of Duchenne Muscular Dystrophy van Putten, Maaike Young, Courtney van den Berg, Sjoerd Pronk, Amanda Hulsker, Margriet Karnaoukh, Tatyana G Vermue, Rick van Dijk, Ko Willems de Kimpe, Sjef Aartsma-Rus, Annemieke Mol Ther Nucleic Acids Original Article Antisense oligonucleotides (AONs) used to reframe dystrophin mRNA transcripts for Duchenne muscular dystrophy (DMD) patients are tested in clinical trials. Here, AONs are administered subcutaneously and intravenously, while the less invasive oral route would be preferred. Oral delivery of encapsulated AONs supplemented with a permeation enhancer, sodium caprate, has been successfully used to target tumor necrosis factor (TNF)-α expression in liver. To test the feasibility of orally delivered AONs for DMD, we applied 2′-O-methyl phosphorothioate AONs (with or without sodium caprate supplementation) directly to the intestine of mdx mice and compared pharmacokinetics and -dynamics with intravenous, intraperitoneal, and subcutaneous delivery. Intestinally infused AONs were taken up, but resulted in lower plasma levels compared to other delivery routes, although bioavailability could be largely improved by supplementation of sodium caprate. After intestinal infusion, AON levels in all tissues were lower than for other administration routes, as were the ratios of target versus nontarget organ levels, except for diaphragm and heart where comparable levels and ratios were observed. For each administration route, low levels of exon skipping in triceps was observed 3 hours post-AON administration. These data suggest that oral administration of naked 2′-O-methyl phosphorothioate AONs may be feasible, but only when high AON concentrations are used in combination with sodium caprate. Nature Publishing Group 2014-11 2014-11-18 /pmc/articles/PMC4459548/ /pubmed/25405468 http://dx.doi.org/10.1038/mtna.2014.62 Text en Copyright © 2014 American Society of Gene & Cell Therapy http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
spellingShingle Original Article
van Putten, Maaike
Young, Courtney
van den Berg, Sjoerd
Pronk, Amanda
Hulsker, Margriet
Karnaoukh, Tatyana G
Vermue, Rick
van Dijk, Ko Willems
de Kimpe, Sjef
Aartsma-Rus, Annemieke
Preclinical Studies on Intestinal Administration of Antisense Oligonucleotides as a Model for Oral Delivery for Treatment of Duchenne Muscular Dystrophy
title Preclinical Studies on Intestinal Administration of Antisense Oligonucleotides as a Model for Oral Delivery for Treatment of Duchenne Muscular Dystrophy
title_full Preclinical Studies on Intestinal Administration of Antisense Oligonucleotides as a Model for Oral Delivery for Treatment of Duchenne Muscular Dystrophy
title_fullStr Preclinical Studies on Intestinal Administration of Antisense Oligonucleotides as a Model for Oral Delivery for Treatment of Duchenne Muscular Dystrophy
title_full_unstemmed Preclinical Studies on Intestinal Administration of Antisense Oligonucleotides as a Model for Oral Delivery for Treatment of Duchenne Muscular Dystrophy
title_short Preclinical Studies on Intestinal Administration of Antisense Oligonucleotides as a Model for Oral Delivery for Treatment of Duchenne Muscular Dystrophy
title_sort preclinical studies on intestinal administration of antisense oligonucleotides as a model for oral delivery for treatment of duchenne muscular dystrophy
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459548/
https://www.ncbi.nlm.nih.gov/pubmed/25405468
http://dx.doi.org/10.1038/mtna.2014.62
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