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

Abstract

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.

Enhanced fear limits behavioral flexibility in Shank2-deficient mice

“…We therefore tested whether DCS would also rescue the behavioral deficits of Shank2-KO mice found in the current study. As repeated administration of DCS causes tachyphylaxis [96][97][98][99] and the drug's half-life in mice is only 23 min [100,101], it would have been difficult to test the effects of DCS on the above-described reversal learning, which takes a relatively long time (1-5 days of training). Given that our results suggested that enhanced fear is the source of reversal learning deficit in male Shank2-KO mice, and eye close responses can be tested within a short period of time, we examined whether DCS could rescue the abnormal eye closure responses (i.e., fear responses) of adult male Shank2-KO mice.…”

In Silico Structural Modeling and Binding Site Analysis of Cerebroside Sulfotransferase (CST): A Therapeutic Target for Developing Substrate Reduction Therapy for Metachromatic Leukodystrophy

“…Substrate reduction therapy (SRT), which has been shown to be effective in other lysosomal storage disorders, may also be a better treatment strategy in MLD. 8,17,18 SRT is a promising oral medication technique in which the inhibition of the protein responsible for the biosynthesis of the substrate of the dysfunctional protein is targeted so that the pathophysiological condition arising due to the accumulation of the substrate can be countered. 8,19,20 In MLD, cerebroside sulfotransferase (CST; EC 2.8.2.11) is a target enzyme for the development of SRT to regulate sulfatide accumulation.…”

“…Hematopoietic stem cell transplant and enzyme replacement therapy are approved therapies for MLD; however, their success varies on a case-to-case basis primarily because of the uncertainty of the disease variant, mutation types, and the stage of disease at the time of transplant. ,,− Above all, the high cost associated with these treatment options deters a larger population from taking advantage of them. Substrate reduction therapy (SRT), which has been shown to be effective in other lysosomal storage disorders, may also be a better treatment strategy in MLD. ,, …”

“…Substrate reduction therapy (SRT), which has been shown to be effective in other lysosomal storage disorders, may also be a better treatment strategy in MLD. 8 , 17 , 18 …”