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Hexose enhances oligonucleotide delivery and exon skipping in dystrophin-deficient mdx mice

Carbohydrate-based infusion solutions are widely used in the clinic. Here we show that co-administration of phosphorodiamidate morpholino oligomers (PMOs) with glucose enhances exon-skipping activity in Duchenne muscular dystrophy (DMD) mdx mice. We identify a glucose–fructose (GF) formulation that...

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Autores principales: Han, Gang, Gu, Ben, Cao, Limin, Gao, Xianjun, Wang, Qingsong, Seow, Yiqi, Zhang, Ning, Wood, Matthew J. A., Yin, HaiFang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4793046/
https://www.ncbi.nlm.nih.gov/pubmed/26964641
http://dx.doi.org/10.1038/ncomms10981
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author Han, Gang
Gu, Ben
Cao, Limin
Gao, Xianjun
Wang, Qingsong
Seow, Yiqi
Zhang, Ning
Wood, Matthew J. A.
Yin, HaiFang
author_facet Han, Gang
Gu, Ben
Cao, Limin
Gao, Xianjun
Wang, Qingsong
Seow, Yiqi
Zhang, Ning
Wood, Matthew J. A.
Yin, HaiFang
author_sort Han, Gang
collection PubMed
description Carbohydrate-based infusion solutions are widely used in the clinic. Here we show that co-administration of phosphorodiamidate morpholino oligomers (PMOs) with glucose enhances exon-skipping activity in Duchenne muscular dystrophy (DMD) mdx mice. We identify a glucose–fructose (GF) formulation that potentiates PMO activity, completely corrects aberrant Dmd transcripts, restores dystrophin levels in skeletal muscles and achieves functional rescue without detectable toxicity. This activity is attributed to enhancement of GF-mediated PMO uptake in the muscle. We demonstrate that PMO cellular uptake is energy dependent, and that ATP from GF metabolism contributes to enhanced cellular uptake of PMO in the muscle. Collectively, we show that GF potentiates PMO activity by replenishing cellular energy stores under energy-deficient conditions in mdx mice. Our findings provide mechanistic insight into hexose-mediated oligonucleotide delivery and have important implications for the development of DMD exon-skipping therapy.
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spelling pubmed-47930462016-03-21 Hexose enhances oligonucleotide delivery and exon skipping in dystrophin-deficient mdx mice Han, Gang Gu, Ben Cao, Limin Gao, Xianjun Wang, Qingsong Seow, Yiqi Zhang, Ning Wood, Matthew J. A. Yin, HaiFang Nat Commun Article Carbohydrate-based infusion solutions are widely used in the clinic. Here we show that co-administration of phosphorodiamidate morpholino oligomers (PMOs) with glucose enhances exon-skipping activity in Duchenne muscular dystrophy (DMD) mdx mice. We identify a glucose–fructose (GF) formulation that potentiates PMO activity, completely corrects aberrant Dmd transcripts, restores dystrophin levels in skeletal muscles and achieves functional rescue without detectable toxicity. This activity is attributed to enhancement of GF-mediated PMO uptake in the muscle. We demonstrate that PMO cellular uptake is energy dependent, and that ATP from GF metabolism contributes to enhanced cellular uptake of PMO in the muscle. Collectively, we show that GF potentiates PMO activity by replenishing cellular energy stores under energy-deficient conditions in mdx mice. Our findings provide mechanistic insight into hexose-mediated oligonucleotide delivery and have important implications for the development of DMD exon-skipping therapy. Nature Publishing Group 2016-03-11 /pmc/articles/PMC4793046/ /pubmed/26964641 http://dx.doi.org/10.1038/ncomms10981 Text en Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International 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/4.0/
spellingShingle Article
Han, Gang
Gu, Ben
Cao, Limin
Gao, Xianjun
Wang, Qingsong
Seow, Yiqi
Zhang, Ning
Wood, Matthew J. A.
Yin, HaiFang
Hexose enhances oligonucleotide delivery and exon skipping in dystrophin-deficient mdx mice
title Hexose enhances oligonucleotide delivery and exon skipping in dystrophin-deficient mdx mice
title_full Hexose enhances oligonucleotide delivery and exon skipping in dystrophin-deficient mdx mice
title_fullStr Hexose enhances oligonucleotide delivery and exon skipping in dystrophin-deficient mdx mice
title_full_unstemmed Hexose enhances oligonucleotide delivery and exon skipping in dystrophin-deficient mdx mice
title_short Hexose enhances oligonucleotide delivery and exon skipping in dystrophin-deficient mdx mice
title_sort hexose enhances oligonucleotide delivery and exon skipping in dystrophin-deficient mdx mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4793046/
https://www.ncbi.nlm.nih.gov/pubmed/26964641
http://dx.doi.org/10.1038/ncomms10981
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