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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 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.

SUBMITTER: Babcock MC

PROVIDER: S-EPMC8280112 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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

Babcock Michael C MC Mikulka Christina R CR Wang Bing B Chandriani Sanjay S Chandra Sundeep S Xu Yue Y Webster Katherine K Feng Ying Y Nelvagal Hemanth R HR Giaramita Alex A Yip Bryan K BK Lo Melanie M Jiang Xuntian X Chao Qi Q Woloszynek Josh C JC Shen Yuqiao Y Bhagwat Shripad S Sands Mark S MS Crawford Brett E BE

Scientific reports 20210714 1

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 ...[more]

PMID: 34262084

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Project description:Cerebroside sulfotransferase (CST) is emerging as an important therapeutic target to develop substrate reduction therapy (SRT) for metachromatic leukodystrophy (MLD), a rare neurodegenerative lysosomal storage disorder. MLD develops with progressive impairment and destruction of the myelin sheath as a result of accumulation of sulfatide around the nerve cells in the absence of its recycling mechanism with deficiency of arylsulfatase A (ARSA). Sulfatide is the product of the catalytic action of cerebroside sulfotransferase (CST), which needs to be regulated under pathophysiological conditions by inhibitor development. To carry out in silico-based preliminary drug screening or for designing new drug candidates, a high-quality three-dimensional (3D) structure is needed in the absence of an experimentally derived three-dimensional crystal structure. In this study, a 3D model of the protein was developed using a primary sequence with the SWISS-MODEL server by applying the top four GMEQ score-based templates belonging to the sulfotransferase family as a reference. The 3D model of CST highlights the features of the protein responsible for its catalytic action. The CST model comprises five β-strands, which are flanked by ten α-helices from both sides as well as form the upside cover of the catalytic pocket of CST. CST has two catalytic regions: PAPS (-sulfo donor) binding and galactosylceramide (-sulfo acceptor) binding. The catalytic action of CST was proposed via molecular docking and molecular dynamic (MD) simulation with PAPS, galactosylceramide (GC), PAPS-galactosylceramide, and PAP. The stability of the model and its catalytic action were confirmed using molecular dynamic simulation-based trajectory analysis. CST response against the inhibition potential of the experimentally reported competitive inhibitor of CST was confirmed via molecular docking and molecular dynamics simulation, which suggested the suitability of the CST model for future drug discovery to strengthen substrate reduction therapy for MLD.

Project description:ObjectiveWe aimed to gain more insight into the pathomechanisms of metachromatic leukodystrophy (MLD), by comparing magnitude and direction of diffusion between patients and controls at diagnosis and during follow-up.MethodsFour late-infantile, 16 juvenile and 8 adult onset MLD patients [of which 13 considered eligible for hematopoietic cell transplantation (HCT)] and 47 controls were examined using diffusion tensor imaging. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were quantified and compared between groups using tract-based spatial statistics (TBSS). Diffusion measures were determined for normal-appearing white matter (NAWM), corpus callosum, thalamus (all based on subject-wise segmentation), and pyramidal tracts, determined with probabilistic tractography. Measures were compared between HCT-eligible patients, non-eligible patients and controls using general linear model and nonparametric permutation analyses (randomise) for TBSS data, considering family-wise error corrected p < 0.05 significant.ResultsThroughout white matter (WM), FA was decreased and MD and RD increased in both patient groups compared to controls, while AD was decreased in NAWM and corpus callosum. In the thalamus, no differences in FA were observed, but all diffusivities were increased in both patient groups. Differences were most pronounced between controls and patients non-eligible for HCT. Longitudinally (median follow-up 3.9 years), diffusion measures remained relatively stable for HCT-treated patients, but were progressively abnormal for non-eligible patients.InterpretationThe observed diffusion measures confirm that brain microstructure is changed in MLD, reflecting different pathological processes including loss of myelin and sulfatide accumulation. The observation of both increased and decreased AD probably reflects a balance between myelin and axonal loss vs. intracellular sulfatide storage in macrophages, depending on region and disease stage.

Project description:Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal disorder caused by the deficiency of arylsulfatase A (ASA), resulting in impaired degradation of sulfatide, an essential sphingolipid of myelin. The clinical manifestations of MLD are characterized by progressive demyelination and subsequent neurological symptoms resulting in severe debilitation. The availability of therapeutic options for treating MLD is limited but expanding with a number of early stage clinical trials already in progress. In the development of therapeutic approaches for MLD, scientists have been facing a number of challenges including blood-brain barrier (BBB) penetration, safety issues concerning therapies targeting the central nervous system, uncertainty regarding the ideal timing for intervention in the disease course, and the lack of more in-depth understanding of the molecular pathogenesis of MLD. Here, we discuss the current status of the different approaches to developing therapies for MLD. Hematopoietic stem cell transplantation has been used to treat MLD patients, utilizing both umbilical cord blood and bone marrow sources. Intrathecal enzyme replacement therapy and gene therapies, administered locally into the brain or by generating genetically modified hematopoietic stem cells, are emerging as novel strategies. In pre-clinical studies, different cell delivery systems including microencapsulated cells or selectively neural cells have shown encouraging results. Small molecules that are more likely to cross the BBB can be used as enzyme enhancers of diverse ASA mutants, either as pharmacological chaperones, or proteostasis regulators. Specific small molecules may also be used to reduce the biosynthesis of sulfatides, or target different affected downstream pathways secondary to the primary ASA deficiency. Given the progressive neurodegenerative aspects of MLD, also seen in other lysosomal diseases, current and future therapeutic strategies will be complementary, whether used in combination or separately at specific stages of the disease course, to produce better outcomes for patients afflicted with this devastating inherited disorder.

Dataset Information

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

Publications

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

Similar Datasets

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