title: Fructose Promotes Uptake and Activity of Oligonucleotides With Different Chemistries in a Context-dependent Manner in mdx Mice.
abstract: Antisense oligonucleotide (AO)-mediated exon-skipping therapeutics shows great promise in correcting frame-disrupting mutations in the DMD gene for Duchenne muscular dystrophy. However, insufficient systemic delivery limits clinical adoption. Previously, we showed that a glucose/fructose mixture augmented AO delivery to muscle in mdx mice. Here, we evaluated if fructose alone could enhance the activities of AOs with different chemistries in mdx mice. The results demonstrated that fructose improved the potency of AOs tested with the greatest effect on phosphorodiamidate morpholino oligomer (PMO), resulted in a 4.25-fold increase in the number of dystrophin-positive fibres, compared to PMO in saline in mdx mice. Systemic injection of lissamine-labeled PMO with fructose at 25 mg/kg led to increased uptake and elevated dystrophin expression in peripheral muscles, compared to PMO in saline, suggesting that fructose potentiates PMO by enhancing uptake. Repeated intravenous administration of PMO in fructose at 50 mg/kg/week for 3 weeks and 50 mg/kg/month for 5 months restored up to 20% of wild-type dystrophin levels in skeletal muscles with improved functions without detectable toxicity, compared to untreated mdx controls. Collectively, we show that fructose can potentiate AOs of different chemistries in vivo although the effect diminished over repeated administration.
authors.affiliation: Department of Cell Biology and Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, China.|Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Medical University General Hospital, Tianjin, 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, Tianjin, 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, Tianjin, China.
authors.forename: Caorui
authors.initials: C
authors.lastname: Lin
authors.affiliation: Department of Cell Biology and Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, 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, Tianjin, China.
authors.forename: Xianjun
authors.initials: X
authors.lastname: Gao
authors.affiliation: Biomedical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, Oregon, USA.
authors.forename: Hong M
authors.initials: HM
authors.lastname: Moulton
authors.affiliation: Molecular Engineering Laboratory, Biomedical Sciences Institutes, Agency for Science Technology and Research, Singapore, Singapore.
authors.forename: Yiqi
authors.initials: Y
authors.lastname: Seow
authors.affiliation: Department of Cell Biology and Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, China.
authors.forename: HaiFang
authors.initials: H
authors.lastname: Yin