2. Academic Validation
  3. Renadirsen, a Novel 2'OMeRNA/ENA® Chimera Antisense Oligonucleotide, Induces Robust Exon 45 Skipping for Dystrophin In Vivo

Renadirsen, a Novel 2'OMeRNA/ENA® Chimera Antisense Oligonucleotide, Induces Robust Exon 45 Skipping for Dystrophin In Vivo

  • Curr Issues Mol Biol. 2021 Sep 25;43(3):1267-1281. doi: 10.3390/cimb43030090.
Kentaro Ito 1,  Hideo Takakusa 2,  Masayo Kakuta 3,  Akira Kanda 1,  Nana Takagi 4,  Hiroyuki Nagase 1,  Nobuaki Watanabe 2,  Daigo Asano 2,  Ryoya Goda 2,  Takeshi Masuda 5,  Akifumi Nakamura 5,  Yoshiyuki Onishi 5,  Toshio Onoda 6,  Makoto Koizumi 5,  Yasuhiro Takeshima 7,  Masafumi Matsuo 8,  Kiyosumi Takaishi 1
Affiliations

Affiliations

  • 1 Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Shinagawa, Tokyo 1408710, Japan.
  • 2 Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Shinagawa, Tokyo 1408710, Japan.
  • 3 Medical Information Department, Daiichi Sankyo Co., Ltd., Chuo, Tokyo 1038426, Japan.
  • 4 Safety and Risk Management Department, Daiichi Sankyo Co., Ltd., Chuo, Tokyo 1038426, Japan.
  • 5 Modality Research Laboratories, Daiichi Sankyo Co., Ltd., Shinagawa, Tokyo 1409710, Japan.
  • 6 Intellectual Property Department, Daiichi Sankyo Co., Ltd., Shinagawa, Tokyo 1409710, Japan.
  • 7 Department of Pediatrics, Hyogo College of Medicine, Nishinomiya 6638501, Japan.
  • 8 Research Center for Locomotion Biology, Kobe Gakuin University, Nishi, Kobe 6512180, Japan.
PMID: 34698059 DOI: 10.3390/cimb43030090
Abstract

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease caused by out-of-frame or nonsense mutation in the Dystrophin gene. It begins with a loss of ambulation between 9 and 14 years of age, followed by various Other symptoms including cardiac dysfunction. Exon skipping of patients' DMD pre-mRNA induced by Antisense Oligonucleotides (AOs) is expected to produce shorter but partly functional Dystrophin proteins, such as those possessed by patients with the less severe Becker muscular dystrophy. We are working on developing modified nucleotides, such as 2'-O,4'-C-ethylene-bridged nucleic acids (ENAs), possessing high nuclease resistance and high affinity for complementary RNA strands. Here, we demonstrate the preclinical characteristics (exon-skipping activity in vivo, stability in blood, pharmacokinetics, and tissue distribution) of renadirsen, a novel AO modified with 2'-O-methyl RNA/ENA chimera phosphorothioate designed for Dystrophin exon 45 skipping and currently under clinical trials. Notably, systemic delivery of renadirsen sodium promoted Dystrophin exon skipping in cardiac muscle, skeletal muscle, and diaphragm, compared with AOs with the same sequence as renadirsen but conventionally modified by PMO and 2'OMePS. These findings suggest the promise of renadirsen sodium as a therapeutic agent that improves not only skeletal muscle symptoms but also Other symptoms in DMD patients, such as cardiac dysfunction.

Keywords

2′-O,4′-C-ethylene-bridged nucleic acid (ENA); Duchenne muscular dystrophy; antisense oligonucleotide; cardiac muscle; dystrophin; exon skipping; renadirsen sodium.

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