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

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.

• Authors: 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
• Journal: Nature communications (Nat Commun) Vol. 13 Issue 1 Pg. 1847 (04 14 2022) ISSN: 2041-1723 [Electronic] England
• PMID: 35422047 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Dystroglycans
• Phosphates
• Prodrugs
• Ribitol

Topics

• Animals
• Humans
• Mice
• Disease Models, Animal
• Dystroglycans
• Muscle, Skeletal
• Muscular Dystrophies (drug therapy, genetics)
• Phosphates
• Prodrugs (pharmacology, therapeutic use)
• Ribitol (therapeutic use)