論文

国際誌
2022年4月14日

CDP-ribitol prodrug treatment ameliorates ISPD-deficient muscular dystrophy mouse model.

Nature communications
  • Hideki Tokuoka
  • Rieko Imae
  • Hitomi Nakashima
  • Hiroshi Manya
  • Chiaki Masuda
  • Shunsuke Hoshino
  • Kazuhiro Kobayashi
  • Dirk J Lefeber
  • Riki Matsumoto
  • Takashi Okada
  • Tamao Endo
  • Motoi Kanagawa
  • Tatsushi Toda
  • 全て表示

13
1
開始ページ
1847
終了ページ
1847
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1038/s41467-022-29473-4

Ribitol-phosphate modification is crucial for the functional maturation of α-dystroglycan. Its dysfunction is associated with muscular dystrophy, cardiomyopathy, and central nervous system abnormalities; however, no effective treatments are currently available for diseases caused by ribitol-phosphate defects. In this study, we demonstrate that prodrug treatments can ameliorate muscular dystrophy caused by defects in isoprenoid synthase domain containing (ISPD), which encodes an enzyme that synthesizes CDP-ribitol, a donor substrate for ribitol-phosphate modification. We generated skeletal muscle-selective Ispd conditional knockout mice, leading to a pathogenic reduction in CDP-ribitol levels, abnormal glycosylation of α-dystroglycan, and severe muscular dystrophy. Adeno-associated virus-mediated gene replacement experiments suggested that the recovery of CDP-ribitol levels rescues the ISPD-deficient pathology. As a prodrug treatment strategy, we developed a series of membrane-permeable CDP-ribitol derivatives, among which tetraacetylated CDP-ribitol ameliorated the dystrophic pathology. In addition, the prodrug successfully rescued abnormal α-dystroglycan glycosylation in patient fibroblasts. Consequently, our findings provide proof-of-concept for supplementation therapy with CDP-ribitol and could accelerate the development of therapeutic agents for muscular dystrophy and other diseases caused by glycosylation defects.

リンク情報
DOI
https://doi.org/10.1038/s41467-022-29473-4
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/35422047
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9010444
ID情報
  • DOI : 10.1038/s41467-022-29473-4
  • PubMed ID : 35422047
  • PubMed Central 記事ID : PMC9010444

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