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


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.

SUBMITTER: Han G 

PROVIDER: S-EPMC4793046 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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

Han Gang G   Gu Ben B   Cao Limin L   Gao Xianjun X   Wang Qingsong Q   Seow Yiqi Y   Zhang Ning N   Wood Matthew J A MJ   Yin HaiFang H  

Nature communications 20160311


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 attr  ...[more]

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