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Nat Commun. 2016 Mar 11;7:10981. doi: 10.1038/ncomms10981.

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

Author information

1
Department of Cell Biology and Research Center of Basic Medical Science, Tianjin Medical University, Qixiangtai Road, Heping District, Tianjin 300070, China.
2
Molecular Engineering Laboratory, Agency for Science Technology and Research, Biomedical Sciences Institutes, 61 Biopolis Way, Singapore 138668, Singapore.
3
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.

Abstract

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.

PMID:
26964641
PMCID:
PMC4793046
DOI:
10.1038/ncomms10981
[Indexed for MEDLINE]
Free PMC Article

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