A European Consortium for Lysosomal Storage Diseases.

Lysosomes are membrane-enclosed compartments, filled with hydrolytic enzymes that are used for the degradation of macromolecules. Proteins and other substrates are delivered to the lysosomes by various pathways including endocytosis, and autophagy, a pathway utilized by the cell for the disposal of obsolete parts.
Many steps are necessary for the correct synthesis and processing of lysosomal enzymes.

Lysosomal Storage Disorders (LSDs) are caused by genetic defects that affect the synthesis or processing of lysosomal hydrolases. Therefore, a lysosomal disorder can be due to a defect in a specific hydrolase, by deficiencies in activator proteins, in the receptors or in the trafficking of enzymes.

The EUCLYD consortium will be focusing on four specific LSDs, namely Gaucher disease, Pompe disease, Mucopolysaccharidosis VI (MPS VI) and Multiple Sulfatase Deficiency (MSD), as prototypes of disorders with different stored materials in various organs and tissues outside the CNS.

The issues to be investigated in the proposed project are: i. pathophysiology and mechanisms underlying the symptoms and leading to devastating clinical consequences; ii. natural history, and iii. testing of novel therapeutic approaches. These issues will be addressed by patients studies and with animal models recapitulating the phenotype of LSDs.

Recent advances in the pathophysiology of LSDs point to the role of secondary processes triggered by substrate storage. A better understanding of these processes is crucial to identify new targets of therapy.

Enzyme replacement and substrate reduction therapies were successfully introduced in the treatment of specific LSDs. However, pilot clinical trials should be supported by post-marketing studies to further assess the efficacy of these therapies and to develop standardized treatment protocols. To this purpose, a precise knowledge of the natural history of LSDs is essential.

Novel therapeutic strategies, such as enzyme enhancement and gene therapy, are still under investigation in cell systems and in animal models. EUCLYD will provide further testing of these approaches in order to translate state-of-the-art knowledge into clinical applications and reach patient’s bedside.