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

Juri Hasegawa, Tetsuya Nagata (), Kensuke Ihara, Jun Tanihata, Satoe Ebihara, Kie Yoshida-Tanaka, Mitsugu Yanagidaira, Masahiro Ohara, Asuka Sasaki, Miyu Nakayama, Syunsuke Yamamoto, Takashi Ishii, Rintaro Iwata-Hara, Mitsuru Naito, Kanjiro Miyata, Fumika Sakaue and Takanori Yokota ()
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Juri Hasegawa: Tokyo Medical and Dental University
Tetsuya Nagata: Tokyo Medical and Dental University
Kensuke Ihara: Tokyo Medical and Dental University
Jun Tanihata: The Jikei University School of Medicine
Satoe Ebihara: Tokyo Medical and Dental University
Kie Yoshida-Tanaka: Tokyo Medical and Dental University
Mitsugu Yanagidaira: Tokyo Medical and Dental University
Masahiro Ohara: Tokyo Medical and Dental University
Asuka Sasaki: Tokyo Medical and Dental University
Miyu Nakayama: Takeda Pharmaceutical Company Limited
Syunsuke Yamamoto: Takeda Pharmaceutical Company Limited
Takashi Ishii: Tokyo Medical and Dental University
Rintaro Iwata-Hara: Tokyo Medical and Dental University
Mitsuru Naito: University of Tokyo
Kanjiro Miyata: University of Tokyo
Fumika Sakaue: Tokyo Medical and Dental University
Takanori Yokota: Tokyo Medical and Dental University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48204-5

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