Long-Term Morpholino Oligomers in Hexose Elicits Long-Lasting Therapeutic Improvements in mdx Mice.

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.

• Authors: Gang Han, Caorui Lin, Hanhan Ning, Xianjun Gao, HaiFang Yin
• Journal: Molecular therapy. Nucleic acids (Mol Ther Nucleic Acids) Vol. 12 Pg. 478-489 (Sep 07 2018) ISSN: 2162-2531 [Print] United States
• PMID: 30195785 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.