Future perspectives for glycolipid research in medicine

Abstract

Medical interest in glycolipids has been mainly directed to the rare and complex glycosphingolipid storage disorders that are principally caused by unitary deficiencies of lysosomal acid hydrolases. However, glycolipids are critical components of cell membranes and occur within newly described membrane domains known as lipid rafts. Glycolipids are components of important antigen systems and membrane receptors; they participate in intracellular signalling mechanisms and may be presented to the immune system in the context of the novel CD1 molecules present on T lymphocytes. A knowledge of their mechanism of action in the control of cell growth and survival as well as developmental pathways is likely to shed light on the pathogenesis of the glycosphingolipid storage disorders as well as the role of lipid second messengers in controlling cell mobility and in the mobilization of intracellular calcium stores (a biological role widely postulated particularly for the lysosphingolipid metabolite sphingosine 1-phosphate). Other sphingolipid metabolites such as ceramide 1-phosphate may be involved in apoptotic responses and in phagocytosis and synaptic vesicle formation. The extraordinary pharmaceutical success of enzymatic complementation for Gaucher's disease using macrophage-targeted human glucocerebrosidase has focused further commercial interest in other glycolipid storage diseases: the cost of targeted enzyme therapy and its failure to restore lysosomal enzymatic deficiencies in the brain has also stimulated interest in the concept of substrate reduction therapy using diffusible inhibitory molecules. Successful clinical trials of the iminosugar Nbutyldeoxynojirimycin in type 1 Gaucher's disease prove the principle of substrate reduction therapy and have attracted attention to this therapeutic method. They will also foster important further experiments into the use of glycolipid synthesis inhibitors for the severe neuronopathic glycosphingolipidoses, for which no definitive treatment is otherwise available. Future glycolipid research in medicine will be directed to experiments that shed light on the role of sphingolipids in signalling pathways, and in the comprehensive characterization and their secretory products in relation to the molecular pathogenesis of the storage disorders; experiments of use to improve the efficiency of complementing enzymatic delivery to the lysosomal compartment of storage cells are also needed. Further systematic screening for inhibitory compounds with specific actions in the pathways of glycosphingolipid biosynthesis will undoubtedly lead to clinical trials in the neuronopathic storage disorders and to wider applications in the fields of immunity and cancer biology.

Recent Advances in the Design of Self‐Delivery Amphiphilic Drugs and Vaccines

“…Their biological functions include maintaining the membrane stability, promoting adhesion, and facilitating cell–pathogen recognition as well as signaling . Medical interest in using synthetic glycolipids are diverse, ranging from antibiotics to antigen presentation and immune stimulation . Amphiphilic carbohydrate derivatives have been investigated for their antimicrobial activity.…”

Characterization of Gaucher disease bone marrow mesenchymal stromal cells reveals an altered inflammatory secretome

“…12,13 Ceramide and sphingosine-1-phosphate (S1P) have inflammation modulation properties and have been proposed to be involved in Gaucher disease pathophysiology. 14,15 Moreover, S1P accumulation has recently been implicated in the neuronal pathology of Sandhoff disease, 16 and decreased lysosomal sphingosine was implicated in the early pathophysiology of NiemannPick type C disease, 17 rendering the study of these molecules compelling in sphingolipid storage disorders.…”

CCL18: A urinary marker of Gaucher cell burden in Gaucher patients

“…Increased plasma levels of these proteins give an indication of the total body load of storage cells. Determination of plasma chitotriosidase is already widely used and recommended for optimization of clinical management of Gaucher disease Cox 2003;Baldellou et al 2004). Plasma CCL18 may act as a valuable alternative surrogate marker for storage cells in the case of Gaucher patients who are deficient in chitotriosidase Deegan et al 2005).…”