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

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 () and Tatsushi Toda ()
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Hideki Tokuoka: Kobe University Graduate School of Medicine
Rieko Imae: Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology
Hitomi Nakashima: Kobe University Graduate School of Medicine
Hiroshi Manya: Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology
Chiaki Masuda: Nippon Medical School
Shunsuke Hoshino: Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology
Kazuhiro Kobayashi: Kobe University Graduate School of Medicine
Dirk J. Lefeber: Radboud University Medical Center, Nijmegen, the Netherlands; Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center
Riki Matsumoto: Division of Neurology, Kobe University Graduate School of Medicine
Takashi Okada: The Institute of Medical Science, The University of Tokyo
Tamao Endo: Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology
Motoi Kanagawa: Kobe University Graduate School of Medicine
Tatsushi Toda: The University of Tokyo

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-29473-4

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