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

Gang Han, Ben Gu, Limin Cao, Xianjun Gao, Qingsong Wang, Yiqi Seow, Ning Zhang, Matthew J. A. Wood () and HaiFang Yin ()
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Gang Han: Tianjin Medical University
Ben Gu: Tianjin Medical University
Limin Cao: Tianjin Medical University
Xianjun Gao: Tianjin Medical University
Qingsong Wang: Tianjin Medical University
Yiqi Seow: Molecular Engineering Laboratory, Agency for Science Technology and Research, Biomedical Sciences Institutes
Ning Zhang: Tianjin Medical University
Matthew J. A. Wood: Anatomy and Genetics, University of Oxford
HaiFang Yin: Tianjin Medical University

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10981

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