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  • Title: Long-Term Morpholino Oligomers in Hexose Elicits Long-Lasting Therapeutic Improvements in mdx Mice.
    Author: Han G, Lin C, Ning H, Gao X, Yin H.
    Journal: Mol Ther Nucleic Acids; 2018 Sep 07; 12():478-489. PubMed ID: 30195785.
    Abstract:
    Approval of antisense oligonucleotide eteplirsen highlights the promise of exon-skipping therapeutics for Duchenne muscular dystrophy patients. However, the limited efficacy of eteplirsen underscores the importance to improve systemic delivery and efficacy. Recently, we demonstrated that a glucose and fructose (GF) delivery formulation effectively potentiates phosphorodiamidate morpholino oligomer (PMO). Considering the clinical potential of GF, it is important to determine the long-term compatibility and efficacy with PMO in mdx mice prior to clinical translation. Here, we report that yearlong administration of a clinically applicable PMO dose (50 mg/kg/week for 3 weeks followed by 50 mg/kg/month for 11 months) with GF elicited sustainably high levels of dystrophin expression in mdx mice, with up to 45% of the normal level of dystrophin restored in most peripheral muscles without any detectable toxicity. Importantly, PMO-GF resulted in phenotypical rescue and mitochondrial biogenesis with functional improvement. Carbohydrate metabolites measurements revealed improved metabolic and energetic conditions after PMO-GF treatment in mdx mice without metabolic anomaly. Collectively, our study shows PMO-GF's ability to elicit long-lasting therapeutic effects with tolerable toxicity and represents a new treatment modality for Duchenne muscular dystrophy, and provides guidelines for antisense oligonucleotides with GF in clinical use.
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