Miglustat: Substrate Reduction Therapy for Lysosomal Storage Disorders Associated with Primary Central Nervous System Involvement

2012 ◽  
Vol 1 (1) ◽  
pp. 77-82
Author(s):  
Gregory M. Pastores
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Central Nervous System Involvement ◽  
Lysosomal Storage Disorders ◽  
Substrate Reduction Therapy ◽  
Lysosomal Storage ◽  
System Involvement ◽  
Substrate Reduction ◽  
Storage Disorders

scholarly journals Small–molecule therapeutics for the treatment of glycolipid lysosomal storage disorders

2003 ◽  
Vol 358 (1433) ◽  
pp. 927-945 ◽  
Author(s):  
Terry D. Butters ◽  
Howard R. Mellor ◽  
Keishi Narita ◽  
Raymond A. Dwek ◽  
Frances M. Platt
Keyword(s):  
Catalytic Activity ◽  
Lysosomal Storage Disorders ◽  
Substrate Reduction Therapy ◽  
Lysosomal Storage ◽  
Substrate Reduction ◽  
Treatment Demand ◽  
Small Molecule Therapeutics ◽  
Storage Disorders

Glycosphingolipid (GSL) lysosomal storage disorders are a small but challenging group of human diseases to treat. Although these disorders appear to be monogenic in origin, where the catalytic activity of enzymes in GSL catabolism is impaired, the clinical presentation and severity of disease are heterogeneous. Present attitudes to treatment demand individual therapeutics designed to match the specific disease–related gene defect; this is an acceptable approach for those diseases with high frequency, but it lacks viability for extremely rare conditions. An alternative therapeutic approach termed ‘substrate deprivation’ or ‘substrate reduction therapy’ (SRT) aims to balance cellular GSL biosynthesis with the impairment in catalytic activity seen in lysosomal storage disorders. The development of N–alkylated iminosugars that have inhibitory activity against the first enzyme in the pathway for glucosylating sphingolipid in eukaryotic cells, ceramide–specific glucosyltransferase, offers a generic therapeutic for the treatment of all glucosphingolipidoses. The successful use of N–alkylated iminosugars to establish SRT as an alternative therapeutic strategy has been demonstrated in in vitro , in vivo and in clinical trials for type 1 Gaucher disease. The implications of these studies and the prospects of improvement to the design of iminosugar compounds for treating Gaucher and other GSL lysosomal storage disorders will be discussed.

Treatments for lysosomal storage disorders

2010 ◽  
Vol 38 (6) ◽  
pp. 1465-1468 ◽  
Author(s):  
Robin Lachmann
Keyword(s):  
Genetic Disorders ◽  
Lysosomal Storage Disorders ◽  
Substrate Reduction Therapy ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Haemopoietic Stem Cell ◽  
Substrate Reduction ◽  
Haemopoietic Stem Cell Transplantation ◽  
Late Stages ◽  
Storage Disorders

There are over 70 human diseases that are caused by defects in various aspects of lysosomal function. Until 20 years ago, the only specific therapy available for lysosomal storage disorders was allogeneic haemopoietic stem cell transplantation. Over the last two decades, there has been remarkable progress and there are now licensed treatments for seven of these diseases. In some cases, a choice of agents is available. For selected enzyme-deficiency disordes, ERT (enzyme-replacement therapy) has proved to be highly effective. In other cases, ERT has been less impressive, and it seems that it is not possible to efficiently deliver recombinant enzyme to all tissues. These difficulties have led to the development of other small-molecule-based therapies, and a drug for SRT (substrate-reduction therapy) is now licensed and potential chaperone molecules for ERT are in the late stages of clinical development. Nonetheless, there is still significant unmet clinical need, particularly when it comes to treating LSDs which affect the brain. LSDs have led the way in the development of treatment for genetic disorders, and it seems likely that there will be further therapeutic innovations in the future.

Central nervous system therapy for lysosomal storage disorders

2008 ◽  
Vol 24 (3-4) ◽  
pp. E12 ◽  
Author(s):  
Gregory M. Enns ◽  
Stephen L. Huhn
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Brain Dysfunction ◽  
Lysosomal Storage Disorders ◽  
Lysosomal Storage ◽  
Systemic Involvement ◽  
Enzyme Replacement ◽  
System Therapy ◽  
Central Nervous System Impairment ◽  
Storage Disorders

✓ Most lysosomal storage disorders are characterized by progressive central nervous system impairment, with or without systemic involvement. Affected individuals have an array of symptoms related to brain dysfunction, the most devastating of which is neurodegeneration following a period of normal development. The blood–brain barrier has represented a significant impediment to developing therapeutic approaches to treat brain disease, but novel approaches—including enzyme replacement, small-molecule, gene, and cell-based therapies—have given children afflicted by these conditions and those who care for them hope for the future.

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