Press Release

Heteroduplex oligonucleotide technology boosts oligonucleotide splice switching activity of morpholino oligomers in a Duchenne muscular dystrophy mouse model

September 26, 2024

Abstract

The approval of splice-switching oligonucleotides with phosphorodiamidate morpholino oligomers (PMOs) for treating Duchenne muscular dystrophy (DMD) has advanced the field of oligonucleotide therapy. Despite this progress, PMOs encounter challenges such as poor tissue uptake, particularly in the heart, diaphragm, and central nervous system (CNS), thereby affecting patient’s prognosis and quality of life. To address these limitations, we have developed a PMOs-based heteroduplex oligonucleotide (HDO) technology. This innovation involves a lipid-ligand-conjugated complementary strand hybridized with PMOs, significantly enhancing delivery to key tissues in mdx mice, normalizing motor functions, muscle pathology, and serum creatine kinase by restoring internal deleted dystrophin expression. Additionally, PMOs-based HDOs normalized cardiac and CNS abnormalities without adverse effects. Our technology increases serum albumin binding to PMOs and improves blood retention and cellular uptake. Here we show that PMOs-based HDOs address the limitations in oligonucleotide therapy for DMD and offer a promising approach for diseases amenable to exon-skipping therapy.

Journal Article

JOURNAL:Nature Communications

TITLE:Heteroduplex oligonucleotide technology boosts oligonucleotide splice switching activity of morpholino oligomers in a Duchenne muscular dystrophy mouse model

DOI:https://doi.org/10.1038/s41467-024-48204-5

Correspondence to

Takanori Yokota, Professor

Department of Neurology and Neurological Science,
Graduate School of Medical and Dental Sciences,
Tokyo Medical and Dental University(TMDU)
E-mail:tak-yokota.nuro(at)tmd.ac.jp

Tetsuya Nagata, Professor

NucleoTIDE and PepTIDE Drug Discovery Center,
Institute of Research,
Tokyo Medical and Dental University(TMDU)
E-mail:t-naga.nuro (at) tmd.ac.jp

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