Improving our understanding of lysosomal disorders
Lysosomal storage disorders (LSDs) are caused by genetic defects in lysosomal enzymes, leading to an intracellular accumulation of undegraded cellular substrates. The result is a range of pathological phenotypes depending on the metabolite. Studying the pathophysiology of various LSDs such as multiple sulfatase deficiency (MSD), Gaucher disease, Pompe disease(PD) and mucopolysaccharidosis (MPS VI) was the subject of the EU-funded project 'A European consortium for lysosomal disorders' (EUCLYD). The ultimate goal was to study the mechanisms that explain disease phenotype and the effects of metabolite accumulation. An important achievement of the consortium was the discovery of a common gene regulatory network that controls lysosomal biogenesis and function mediated by the transcription factor TFEB. Overexpression of TFEB rescued pathologic storage and restored normal cellular morphology in LSD mouse models. Work on the glycogen-accumulating PD revealed a number of cellular abnormalities in patients, including increased autophagy and aberrant trafficking and recycling of the cation-independent mannose-6-phosphate receptor (CI-MPR). Mutation analysis of the acid alpha glucosidase (GAA) gene in Pompe patients revealed a strong correlation with disease phenotype. Enzyme replacement therapy with recombinant human alpha-glucosidase (rhGAA) is currently the only approved treatment for PD but the emergence of neutralising antibodies raises the issue of efficacy. EUCLYD partners developed an enhancement therapy approach for residual GAA activity, which however may be limited to certain GAA genotypes only. With respect to Gaucher disease – which is characterised by an abnormal accumulation of sphingolipids due to a deficiency of beta-glucocerebrosidase – researchers found a significant upregulation of the chemokine CCL18 linked to the appearance of osteonecrosis. Using a mouse model of the disease, the consortium optimised a gene therapy approach that aimed to deliver the wild-type gene of glucosylceramidase into hematopoietic stem cells. At the same time, various inhibitors were tested for their efficiency to alleviate disease symptoms. Clinical work on patients with MPS VI with abnormal storage of glycosaminoglycans (GAGs) resulted in improved protocols for the diagnosis and clinical follow-up of patients with this disease. A gene therapy protocol in animal models of MPS VI was also established that entailed the delivery and long-term sustained release of arylsulfatase B by the liver. Alternative strategies with substrate-reducing agents proved effective in cells from MPS VI patients. Overall, the EUCLYD project provided important insight into the mechanisms underlying LSDs and into the secondary effects caused by metabolite accumulation. Through the identification of disease biomarkers and the development of various treatment strategies, partners hope to modify the clinical course of these debilitating diseases.
