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New therapeutics for the treatment of glycosphingolipid lysosomal storage diseases
T D Butters1, R A Dwek, F M Platt
1Glycobiology Institute, Department of Biochemistry, Oxford University, Oxford, UK.
Abstract:
Glycosphingolipid lysosomal storage diseases are a small but challenging group of human disorders to treat. Although these appear to be monogenic disorders where the catalytic activity of enzymes in glycosphingolipid catabolism is impaired, the presentation and severity of disease is heterogeneous. Treatment is often restricted to palliative care, but in some disorders enzyme replacement does offer a significant clinical improvement of disease severity. An alternative therapeutic approach termed "substrate deprivation" or "substrate reduction therapy" (SRT) aims to reduce cellular glycosphingolipid biosynthesis to match the impairment in catalytic activity seen in lysosomal storage disorders. N-Alkylated imino sugars are nitrogen containing polyhydroxylated heterocycles that have inhibitory activity against the first enzyme in the pathway for glucosylating sphingolipid in eukaryotic cells, ceramide-specific glucosyltransferase. The use of N-alkylated imino sugars to establish SRT as an alternative therapeutic strategy is described in cell culture and gene knockout mouse disease models. One imino sugar, N-butyl-DNJ (NB-DNJ) has been used in clinical trials for type 1 Gaucher disease and has shown to be an effective and safe therapy for this disorder. The results of these trials and the prospects of improvement to the design of imino sugar compounds for treating Gaucher and other glycosphingolipid lysosomal storage disorders will be discussed.
Insights
Substrate reduction therapy (SRT) offers a new approach for glycosphingolipid lysosomal storage diseases by reducing cellular biosynthesis. N-alkylated imino sugars, like N-butyl-DNJ, show promise as effective and safe treatments, particularly for Gaucher disease.
Area of Science:
- Biochemistry
- Genetics
- Pharmacology
Background:
- Glycosphingolipid lysosomal storage diseases present heterogeneous phenotypes despite monogenic origins.
- Current treatments are often palliative, with enzyme replacement therapy (ERT) showing limited success.
- Substrate reduction therapy (SRT) aims to balance glycosphingolipid biosynthesis with impaired catabolism.
Purpose of the Study:
- To explore N-alkylated imino sugars as a novel therapeutic strategy for glycosphingolipid lysosomal storage disorders.
- To evaluate the efficacy of SRT using imino sugars in preclinical models.
- To discuss the clinical application and future development of imino sugar-based therapies.
Main Methods:
- Utilized cell culture and gene knockout mouse models to investigate SRT.
- Assessed the inhibitory activity of N-alkylated imino sugars against ceramide-specific glucosyltransferase.
- Reviewed clinical trial data for N-butyl-DNJ in type 1 Gaucher disease.
Main Results:
- N-alkylated imino sugars demonstrated inhibitory activity against a key enzyme in glycosphingolipid biosynthesis.
- SRT using N-alkylated imino sugars proved effective in cell culture and mouse models.
- N-butyl-DNJ showed significant efficacy and safety in clinical trials for type 1 Gaucher disease.
Conclusions:
- SRT represents a viable therapeutic alternative for glycosphingolipid lysosomal storage disorders.
- N-alkylated imino sugars are promising candidates for developing improved SRT treatments.
- Further optimization of imino sugar compounds could benefit Gaucher disease and other related lysosomal storage disorders.
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