TY - JOUR
T1 - Substrate reduction therapy for Krabbe disease and metachromatic leukodystrophy using a novel ceramide galactosyltransferase inhibitor
AU - Babcock, Michael C.
AU - Mikulka, Christina R.
AU - Wang, Bing
AU - Chandriani, Sanjay
AU - Chandra, Sundeep
AU - Xu, Yue
AU - Webster, Katherine
AU - Feng, Ying
AU - Nelvagal, Hemanth R.
AU - Giaramita, Alex
AU - Yip, Bryan K.
AU - Lo, Melanie
AU - Jiang, Xuntian
AU - Chao, Qi
AU - Woloszynek, Josh C.
AU - Shen, Yuqiao
AU - Bhagwat, Shripad
AU - Sands, Mark S.
AU - Crawford, Brett E.
N1 - Funding Information:
We would like to acknowledge HD Bio for conducting the CGT enzyme and cellular assays and screening the bioactive lipid library. ChemPartner for conducting the synthesis of the CGT inhibitors, mouse PK studies, MLD mouse studies, and accompanying bioanalysis. Dr. Mike Gelb and Xinying Hong for running the ARSA assays. Dr. Gieselmann for providing the MLD mouse model. Jax Bar Harbor for conducting the wild-type mouse tolerability studies including NCV, G-ratios, clinical pathology, and wire hang. EPL for evaluating histopathological changes including scoring of the vacuolation. Dean and Teryn Suhr from the MLD Foundation for advice and support. This work was supported by BioMarin Pharmaceutical Inc. and the National Institutes of Health NIH R01 NS100779 (MSS).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85111160321&partnerID=8YFLogxK
U2 - 10.1038/s41598-021-93601-1
DO - 10.1038/s41598-021-93601-1
M3 - Article
C2 - 34262084
AN - SCOPUS:85111160321
SN - 2045-2322
VL - 11
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 14486
ER -