Brain Penetrable Inhibitors of Ceramide Galactosyltransferase for the Treatment of Lysosomal Storage Disorders

Thurairatnam, Sukanthini; Lim, Sungtaek; Barker, Robert H.; Choi-Sledeski, Yong Mi; Hirth, Bradford; Jiang, Jiaren; Macor, John E.; Makino, Elina; Maniar, Sachin; Musick, Kwon; Pribish, James; Munson, Mark

doi:10.1021/acsmedchemlett.0c00120

Cited by 13 publications

(21 citation statements)

References 26 publications

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“…Another potential SRT target for Krabbe disease is ceramide galactosyltransferase (CGT). CGT is the enzyme responsible for the addition of galactose to ceramide and is only one enzymatic step removed from psychosine synthesis [ 40 ]. A new class of brain-penetrable compounds has been described that efficiently inhibit CGT activity [ 40 ].…”

Section: The Evolution and Current Status Of Therapies For Krabbe Diseasementioning

confidence: 99%

Krabbe disease: New hope for an old disease

Bradbury

Bongarzone

Sands

2021

Neuroscience Letters

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Krabbe disease (globoid cell leukodystrophy) is a lysosomal storage disease (LSD) characterized by progressive and profound demyelination. Infantile, juvenile and adult-onset forms of Krabbe disease have been described, with infantile being the most common. Children with an infantile-onset generally appear normal at birth but begin to miss developmental milestones by si x months of age and die by two to four years of age. Krabbe disease is caused by a deficiency of the acid hydrolase galactosylceramidase (GALC) which is responsible for the degradation of galactosylceramides and sphingolipids, which are abundant in myelin membranes. The absence of GALC leads to the to x ic accumulation of galactosylsphingosine (psychosine), a lysoderivative of galactosylceramides, in oligodendrocytes and Schwann cells resulting in demyelination of the central and peripheral nervous systems, respectively. Treatment strategies such as enzyme replacement, substrate reduction, enzyme chaperones, and gene therapy have shown promise in LSDs. Unfortunately, Krabbe disease has been relatively refractory to most single-therapy interventions. Although hematopoietic stem cell transplantation can alter the course of Krabbe disease and is the current standard-of-care, it simply slows the progression, even when initiated in presymptomatic children. However, the recent success of combinatorial therapeutic approaches in small animal models of Krabbe disease and the identification of new pathogenic mechanisms provide hope for the development of effective treatments for this devastating disease. This review provides a brief history of Krabbe disease and the evolution of single and combination therapeutic approaches and discusses new pathogenic mechanisms and how they might impact the development of more effective treatment strategies.

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Section: The Evolution and Current Status Of Therapies For Krabbe Diseasementioning

confidence: 99%

Krabbe disease: New hope for an old disease

Bradbury

Bongarzone

Sands

2021

Neuroscience Letters

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“…The ability to selectively inhibit the synthesis of non-hydroxylated galactosylceramides should be a useful attribute to enable the further understanding of the roles of the different hydroxylated species. Given that CGT inhibitors are actively being pursued as potential SRT therapy for KD and MLD 15 , further studies will be necessary to fully understand how to balance their safety and therapeutic benefit.…”

Section: Discussionmentioning

confidence: 99%

“…The discovery of small molecules that inhibit the synthesis of galactosylceramide-based glycolipids that accumulate in KD and MLD is an area of active research 15 . Studies using small molecule glucosylceramide synthase inhibitors to reduce the abundance of the glycolipids that accumulate in Gaucher disease, Fabry disease, GM1 gangliosidosis, and GM2 gangliosidosis, have demonstrated the benefits of substrate reduction therapy 16 – 20 .…”

Section: Introductionmentioning

confidence: 99%

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

Babcock

Mikulka

Wang

et al. 2021

Sci Rep

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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.

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“…The gene UGT8 encodes for ceramide galactosyltransferase (CGT), which catalyzes the final step for galactosylceramide synthesis. Following a search of 30,000 compounds for their ability to inhibit CGT, a thienopyridine was identified and further optimized, resulting in a drug (compound 19) that is an efficacious in vivo inhibitor of CGT that is both orally bioavailable and enters the CNS ( 60 ). In vivo testing in normal mice revealed that this compound was able to inhibit the production of both galactosylceramide and sulfatide in the brain and kidney ( 60 ).…”

Section: Substrate Reduction Therapy Targeting Ceramide Galactosyltransferasementioning

confidence: 99%

“…Following a search of 30,000 compounds for their ability to inhibit CGT, a thienopyridine was identified and further optimized, resulting in a drug (compound 19) that is an efficacious in vivo inhibitor of CGT that is both orally bioavailable and enters the CNS ( 60 ). In vivo testing in normal mice revealed that this compound was able to inhibit the production of both galactosylceramide and sulfatide in the brain and kidney ( 60 ). Additional in vivo studies that examine the therapeutic efficacy in mouse models of Krabbe disease and/or metachromatic leukodystrophy are anticipated.…”

Section: Substrate Reduction Therapy Targeting Ceramide Galactosyltransferasementioning

confidence: 99%

Substrate Reduction Therapy for Krabbe Disease: Exploring the Repurposing of the Antibiotic D-Cycloserine

Levine

Tsau

2022

Front. Pediatr.

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Krabbe disease is a lysosomal storage disease that is caused by a deficiency in galactosylceramidase. Infantile onset disease is the most common presentation, which includes progressive neurological deterioration with corresponding demyelination, development of globoid cells, astrocyte gliosis, etc. Hemopoietic stem cell transplantation (HSCT) is a disease modifying therapy, but this intervention is insufficient with many patients still experiencing developmental delays and progressive deterioration. Preclinical studies have used animal models, e.g., twitcher mice, to test different experimental therapies resulting in developments that have led to progressive improvements in the therapeutic impact. Some recent advances have been in the areas of gene therapy and substrate reduction therapy (SRT), as well as using these in combination with HSCT. Unfortunately, new experimental approaches have encountered obstacles which have impeded the translation of novel therapies to human patients. In an effort to identify a safe adjunct therapy, D-cycloserine was tested in preliminary studies in twitcher mice. When administered as a standalone therapy, D-cycloserine was shown to lengthen the lifespan of twitcher mice in a small but significant manner. D-Cycloserine is an FDA approved antibiotic used for drug resistant tuberculosis. It also acts as a partial agonist of the NMDA receptor, which has led to numerous human studies for a range of neuropsychiatric and neurological conditions. In addition, D-cycloserine may inhibit serine palmitoyltransferase (SPT), which catalyzes the rate-limiting step in sphingolipid production. The enantiomer, L-cycloserine, is a much more potent inhibitor of SPT than D-cycloserine. Previously, L-cycloserine was found to act as an effective SRT agent in twitcher mice as both a standalone therapy and as part of combination therapies. L-Cycloserine is not approved for human use, and its potent inhibitory properties may limit its ability to maintain a level of partial inactivation of SPT that is also safe. In theory, D-cycloserine would encompass a much broader dosage range to achieve a safe degree of partial inhibition of SPT, which increases the likelihood it could advance to human studies in patients with Krabbe disease. Furthermore, additional properties of D-cycloserine raise the possibility of other therapeutic mechanisms that could be exploited for the treatment of this disease.

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Brain Penetrable Inhibitors of Ceramide Galactosyltransferase for the Treatment of Lysosomal Storage Disorders

Cited by 13 publications

References 26 publications

Krabbe disease: New hope for an old disease

Krabbe disease: New hope for an old disease

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

Substrate Reduction Therapy for Krabbe Disease: Exploring the Repurposing of the Antibiotic D-Cycloserine

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