Substrate reduction therapy for Krabbe disease and metachromatic leukodystrophy using a novel ceramide galactosyltransferase inhibitor

Abstract Krabbe disease (KD) and metachromatic leukodystrophy (MLD) are caused by accumulation of the glycolipids galactosylceramide (GalCer) and sulfatide and their toxic metabolites psychosine and lysosulfatide, respectively. We discovered a potent and selective small molecule inhibitor (S202) of...

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Autores principales:	Michael C. Babcock, Christina R. Mikulka, Bing Wang, Sanjay Chandriani, Sundeep Chandra, Yue Xu, Katherine Webster, Ying Feng, Hemanth R. Nelvagal, Alex Giaramita, Bryan K. Yip, Melanie Lo, Xuntian Jiang, Qi Chao, Josh C. Woloszynek, Yuqiao Shen, Shripad Bhagwat, Mark S. Sands, Brett E. Crawford
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b4baa35aa3c440d78cac8c75d11ceb69
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spelling	oai:doaj.org-article:b4baa35aa3c440d78cac8c75d11ceb692021-12-02T16:14:09ZSubstrate reduction therapy for Krabbe disease and metachromatic leukodystrophy using a novel ceramide galactosyltransferase inhibitor10.1038/s41598-021-93601-12045-2322https://doaj.org/article/b4baa35aa3c440d78cac8c75d11ceb692021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-93601-1https://doaj.org/toc/2045-2322Abstract Krabbe disease (KD) and metachromatic leukodystrophy (MLD) are caused by accumulation of the glycolipids galactosylceramide (GalCer) and sulfatide and their toxic metabolites psychosine and lysosulfatide, respectively. We discovered a potent and selective small molecule inhibitor (S202) of ceramide galactosyltransferase (CGT), the key enzyme for GalCer biosynthesis, and characterized its use as substrate reduction therapy (SRT). Treating a KD mouse model with S202 dose-dependently reduced GalCer and psychosine in the central (CNS) and peripheral (PNS) nervous systems and significantly increased lifespan. Similarly, treating an MLD mouse model decreased sulfatides and lysosulfatide levels. Interestingly, lower doses of S202 partially inhibited CGT and selectively reduced synthesis of non-hydroxylated forms of GalCer and sulfatide, which appear to be the primary source of psychosine and lysosulfatide. Higher doses of S202 more completely inhibited CGT and reduced the levels of both non-hydroxylated and hydroxylated forms of GalCer and sulfatide. Despite the significant benefits observed in murine models of KD and MLD, chronic CGT inhibition negatively impacted both the CNS and PNS of wild-type mice. Therefore, further studies are necessary to elucidate the full therapeutic potential of CGT inhibition.Michael C. BabcockChristina R. MikulkaBing WangSanjay ChandrianiSundeep ChandraYue XuKatherine WebsterYing FengHemanth R. NelvagalAlex GiaramitaBryan K. YipMelanie LoXuntian JiangQi ChaoJosh C. WoloszynekYuqiao ShenShripad BhagwatMark S. SandsBrett E. CrawfordNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Michael C. Babcock Christina R. Mikulka Bing Wang Sanjay Chandriani Sundeep Chandra Yue Xu Katherine Webster Ying Feng Hemanth R. Nelvagal Alex Giaramita Bryan K. Yip Melanie Lo Xuntian Jiang Qi Chao Josh C. Woloszynek Yuqiao Shen Shripad Bhagwat Mark S. Sands Brett E. Crawford Substrate reduction therapy for Krabbe disease and metachromatic leukodystrophy using a novel ceramide galactosyltransferase inhibitor
description	Abstract Krabbe disease (KD) and metachromatic leukodystrophy (MLD) are caused by accumulation of the glycolipids galactosylceramide (GalCer) and sulfatide and their toxic metabolites psychosine and lysosulfatide, respectively. We discovered a potent and selective small molecule inhibitor (S202) of ceramide galactosyltransferase (CGT), the key enzyme for GalCer biosynthesis, and characterized its use as substrate reduction therapy (SRT). Treating a KD mouse model with S202 dose-dependently reduced GalCer and psychosine in the central (CNS) and peripheral (PNS) nervous systems and significantly increased lifespan. Similarly, treating an MLD mouse model decreased sulfatides and lysosulfatide levels. Interestingly, lower doses of S202 partially inhibited CGT and selectively reduced synthesis of non-hydroxylated forms of GalCer and sulfatide, which appear to be the primary source of psychosine and lysosulfatide. Higher doses of S202 more completely inhibited CGT and reduced the levels of both non-hydroxylated and hydroxylated forms of GalCer and sulfatide. Despite the significant benefits observed in murine models of KD and MLD, chronic CGT inhibition negatively impacted both the CNS and PNS of wild-type mice. Therefore, further studies are necessary to elucidate the full therapeutic potential of CGT inhibition.
format	article
author	Michael C. Babcock Christina R. Mikulka Bing Wang Sanjay Chandriani Sundeep Chandra Yue Xu Katherine Webster Ying Feng Hemanth R. Nelvagal Alex Giaramita Bryan K. Yip Melanie Lo Xuntian Jiang Qi Chao Josh C. Woloszynek Yuqiao Shen Shripad Bhagwat Mark S. Sands Brett E. Crawford
author_facet	Michael C. Babcock Christina R. Mikulka Bing Wang Sanjay Chandriani Sundeep Chandra Yue Xu Katherine Webster Ying Feng Hemanth R. Nelvagal Alex Giaramita Bryan K. Yip Melanie Lo Xuntian Jiang Qi Chao Josh C. Woloszynek Yuqiao Shen Shripad Bhagwat Mark S. Sands Brett E. Crawford
author_sort	Michael C. Babcock
title	Substrate reduction therapy for Krabbe disease and metachromatic leukodystrophy using a novel ceramide galactosyltransferase inhibitor
title_short	Substrate reduction therapy for Krabbe disease and metachromatic leukodystrophy using a novel ceramide galactosyltransferase inhibitor
title_full	Substrate reduction therapy for Krabbe disease and metachromatic leukodystrophy using a novel ceramide galactosyltransferase inhibitor
title_fullStr	Substrate reduction therapy for Krabbe disease and metachromatic leukodystrophy using a novel ceramide galactosyltransferase inhibitor
title_full_unstemmed	Substrate reduction therapy for Krabbe disease and metachromatic leukodystrophy using a novel ceramide galactosyltransferase inhibitor
title_sort	substrate reduction therapy for krabbe disease and metachromatic leukodystrophy using a novel ceramide galactosyltransferase inhibitor
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/b4baa35aa3c440d78cac8c75d11ceb69
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Substrate reduction therapy for Krabbe disease and metachromatic leukodystrophy using a novel ceramide galactosyltransferase inhibitor

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