[Current therapeutic strategies in lysosomal disorders]

Abstract

The lysosomal storage disorders (LSD) comprise a heterogeneous group of inborn errors of metabolism. The resulting enzymatic defect leads to accumulation of its substrate in the lysosome. Their clinical patterns reflect the site of substrate storage. Central nervous system involvement is often present in the younger patients affected by the most severe phenotypes. Substantial progress has been made in the pathophysiological knowledge, leading to new therapeutic options in LSD. Enzyme replacement therapy (ERT) is the dominant approach and is actually proposed in six LSD: Gaucher disease, Fabry disease, Pompe disease and mucopolysaccharidoisis (MPS) I (Hurler disease), II (Hunter disease) and VI (Maroteaux-Lamy disease). This treatment reduces lysosomal storage, and sometimes reduces, but most often limits the progression of visceral involvement and of its clinical consequences. However, ERT does not cross the blood-brain barrier and is ineffective on neurological symptoms. In the younger patients with MPS I (Hurler disease) and with selected cases of other LSD, haematopoietic stem cell transplantation remains the optimal option. Other strategies using small molecules are being explored in order to cross the blood-brain barrier. This includes substrate reduction or depletion therapies, which decrease the amount of substrate, and the use of pharmacological chaperones, which enhance the residual activity of the mutant enzyme. Miglustat is the proposed substrate reduction therapy in Niemann-Pick C disease and clinical trials are actually performed in several LSD using other substrate reduction or chaperone drugs.