A novel brain-penetrant oral UGT8 inhibitor decreases in vivo galactosphingolipid biosynthesis in murine Krabbe disease.
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Authors
Zaccariotto, Eva
Cachón-González, María Begoña
Wang, Bing
Lim, Sungtaek
Hirth, Bradford
Park, Hyejung
Fezoui, Malika
Sardi, S Pablo
Mason, Paul
Barker, Robert H
Cox, Timothy M
Publication Date
2022-05Journal Title
Biomed Pharmacother
ISSN
0753-3322
Publisher
Elsevier BV
Volume
149
Number
112808
Pages
112808-112808
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Zaccariotto, E., Cachón-González, M. B., Wang, B., Lim, S., Hirth, B., Park, H., Fezoui, M., et al. (2022). A novel brain-penetrant oral UGT8 inhibitor decreases in vivo galactosphingolipid biosynthesis in murine Krabbe disease.. Biomed Pharmacother, 149 (112808), 112808-112808. https://doi.org/10.1016/j.biopha.2022.112808
Abstract
Krabbe disease is a rare, inherited neurodegenerative disease due to impaired lysosomal β-galactosylceramidase (GALC) activity and formation of neurotoxic β-galactosylsphingosine ('psychosine'). We investigated substrate reduction therapy with a novel brain-penetrant inhibitor of galactosylceramide biosynthesis, RA 5557, in twitcher mice that lack GALC activity and model Krabbe disease. This thienopyridine derivative selectively inhibits uridine diphosphate-galactose glycosyltransferase 8 (UGT8), the final step in the generation of galactosylceramides which are precursors of sulphatide and, in the pathological lysosome, the immediate source of psychosine. Administration of RA 5557, reduced pathologically elevated psychosine concentrations (72-86%) in the midbrain and cerebral cortex in twitcher mice: the inhibitor decreased galactosylceramides by about 70% in midbrain and cerebral cortex in mutant and wild type animals. Exposure to the inhibitor significantly decreased several characteristic inflammatory response markers without causing apparent toxicity to myelin-producing cells in wild type and mutant mice; transcript abundance of oligodendrocyte markers MBP (myelin basic protein) and murine UGT8 was unchanged. Administration of the inhibitor before conception and during several breeding cycles to mice did not impair fertility and gave rise to healthy offspring. Nevertheless, given the unchanged lifespan, it appears that GALC has critical functions in the nervous system beyond the hydrolysis of galactosylceramide and galactosylsphingosine. Our findings support further therapeutic exploration of orally active UGT8 inhibitors in Krabbe disease and related galactosphingolipid disorders. The potent thienopyridine derivative with effective target engagement here studied appears to have an acceptable safety profile in vivo; judicious dose optimization will be needed to ensure efficacious clinical translation.
Sponsorship
Sponsored by Sanofi phamaceuticals but with Cambridge NIHR BRC salary support for one author from Cambridge (Cachon-Gonzalez)
Funder references
National Institute for Health Research (IS-BRC-1215-20014)
Identifiers
External DOI: https://doi.org/10.1016/j.biopha.2022.112808
This record's URL: https://www.repository.cam.ac.uk/handle/1810/335040
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/
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