title: 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.
authors.affiliation: Department of Cell Biology and Research Center of Basic Medical Science, Tianjin Medical University, Qixiangtai Road, Heping District, Tianjin 300070, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Han
authors.affiliation: Department of Cell Biology and Research Center of Basic Medical Science, Tianjin Medical University, Qixiangtai Road, Heping District, Tianjin 300070, China.
authors.forename: Ben
authors.initials: B
authors.lastname: Gu
authors.affiliation: Department of Cell Biology and Research Center of Basic Medical Science, Tianjin Medical University, Qixiangtai Road, Heping District, Tianjin 300070, China.
authors.forename: Limin
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Cell Biology and Research Center of Basic Medical Science, Tianjin Medical University, Qixiangtai Road, Heping District, Tianjin 300070, China.
authors.forename: Xianjun
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Cell Biology and Research Center of Basic Medical Science, Tianjin Medical University, Qixiangtai Road, Heping District, Tianjin 300070, China.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Molecular Engineering Laboratory, Agency for Science Technology and Research, Biomedical Sciences Institutes, 61 Biopolis Way, Singapore 138668, Singapore.
authors.forename: Yiqi
authors.identifier: http://orcid.org/0000-0001-7040-3006
authors.initials: Y
authors.lastname: Seow
authors.affiliation: Department of Cell Biology and Research Center of Basic Medical Science, Tianjin Medical University, Qixiangtai Road, Heping District, Tianjin 300070, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.
authors.forename: Matthew J A
authors.initials: MJ
authors.lastname: Wood
authors.affiliation: Department of Cell Biology and Research Center of Basic Medical Science, Tianjin Medical University, Qixiangtai Road, Heping District, Tianjin 300070, China.
authors.forename: HaiFang
authors.initials: H
authors.lastname: Yin
mesh_terms: D000818:Animals; D016189:Dystrophin / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D005091:Exons; D005632:Fructose / Q000494:pharmacology*; D015316:Genetic Therapy; D005947:Glucose / Q000494:pharmacology*; D006601:Hexoses / Q000494:pharmacology; D007273:Injections, Intramuscular; D051379:Mice; D018101:Mice, Inbred mdx; D060172:Morpholinos / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D012326:RNA Splicing / Q000187:drug effects*; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism
chemical_list: D016189:Dystrophin; D006601:Hexoses; D060172:Morpholinos; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; C085339:apo-dystrophin 1; D005632:Fructose; D005947:Glucose