Gene therapy: prospects for glycolipid storage diseases

In this review, recent studies of membrane lipid transport in sphingolipid (SL) storage disease (SLSD) fibroblasts are summarized. Several fluorescent glycosphingolipid (GSL) analogues are internalized from the plasma membrane via caveolae and are subsequently transported to the Golgi complex of normal fibroblasts, while in 10 different SLSD cell types, these lipids accumulate in endosomes and lysosomes. Additional studies have shown that cholesterol homeostasis is perturbed in multiple SLSDs secondary to accumulation of endogenous SLs, and that mis-targeting of the GSLs is regulated by cellular cholesterol. Golgi targeting of GSLs internalized via caveolae is dependent on microtubules and phosphoinositide 3-kinase(s) and is inhibited by expression of dominant-negative rab7 and rab9 constructs. Overexpression of wild-type rab7 or rab9 (but not rab11) in Niemann-Pick C fibroblasts results in correction of lipid trafficking defects, including restoration of Golgi targeting of fluorescent lactosylceramide and endogenous GM1 ganglioside (monitored by the transport of fluorescent cholera toxin), and a dramatic reduction in accumulation of intracellular cholesterol. These results suggest an approach for restoring normal lipid trafficking in this, and perhaps other, SLSD cell types, and may provide a basis for future therapy of these diseases.

Section: Summary and Future Directionsmentioning

confidence: 99%

Endocytic trafficking of glycosphingolipids in sphingolipid storage diseases

Pagano

2003

“…The rationale for therapeutic intervention of type 1 Gaucher disease is therefore relatively simple: correction (or prevention of ongoing formation) of Gaucher cells. This could be accomplished by: (i) supplementation of macrophages with the enzyme glucocerebrosidase (enzyme replacement therapy; Brady (2003)); (ii) reduction of glycolipid synthesis with specific inhibitors (substrate deprivation or substrate balancing therapy; Butters et al (2003); Platt et al (2003)); or (iii) introduction of glucocerebrosidase cDNA in haemopoietic progenitors of macrophages (gene therapy; Gieselmann et al (2003)). Other more speculative avenues may be the stabilization of specific mutant forms of the enzyme (chemical chaperons or inhibitors of proteolytic degradation) and the manipulation of intralysosomal pH.…”

Section: Therapy Of Type 1 Gaucher Diseasementioning

confidence: 99%

“…Next, the glycoproteins are exported to the Golgi apparatus where, exclusively, some of their oligosaccharide chains obtain mannose-6-phosphate moieties by a two-step process. The phosphomannosyl moieties act as a specific recognition signal (Gieselmann et al 2003). Selective binding of a major fraction of most lysosomal enzymes to cation-dependent or cation-independent MPRs, allows their segregation from the secretory proteins in the trans-Golgi network.…”

Section: Introductionmentioning

confidence: 99%

Biochemistry of glycosphingolipid storage disorders: implications for therapeutic intervention

Aerts

Hollak

Boot

et al. 2003

The physiological importance of the degradative processes in lysosomes is revealed by the existence of at least 40 distinct inherited diseases, the so-called lysosomal storage disorders. Most of these diseases are caused by a deficiency in a single lysosomal enzyme, or essential cofactor, and result in the lysosomal accumulation of one, or sometimes several, natural compounds. The most prevalent subgroup of the lysosomal storage disorders is formed by the sphingolipidoses, inherited disorders that are characterized by excessive accumulation of one or multiple (glyco)sphingolipids. The biology of glycosphingolipids has been extensively discussed in other contributions during this symposium. This review will therefore focus in depth on (type 1) Gaucher disease, a prototypical glycosphingolipidosis. The elucidation of the primary genetic defect, being a deficiency in the lysosomal glucocerebrosidase, is described. Characterization of glucocerebrosidase at protein and gene level has subsequently opened avenues for therapeutic intervention. The development of successful enzyme replacement therapy for type 1 Gaucher disease is discussed. Attention is also paid to the alternative approach of substrate modulation using orally administered inhibitors of glucosylceramide synthesis. Novel developments about the monitoring of age of onset, progression and correction of disease are described. The remaining challenges about pathophysiology of glycosphingolipidoses are discussed in view of further improvements in therapy for these debilitating disorders.

“…We have had a broad conspectus of the different treatments that are available by Professor Gieselmann, particularly in relation to bone marrow transplantation and gene therapy for neurological disorders (Matzner et al 2002;Gieselmann et al 2003). Dr Roscoe Brady has mentioned his classical studies over many years leading to the successful delivery of enzymatic replacement for Gaucher's disease and, latterly, Fabry's disease (Brady 2003).…”

Section: Treatment Of Glycolipid Storage Diseasesmentioning

confidence: 99%

Future perspectives for glycolipid research in medicine

Cox

2003

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.