Pathobiological Insights into the Newly Targeted Therapies of Lysosomal Storage Disorders

Abstract Lysosomal storage disorders (LSDs) are a heterogeneous group of inborn errors of metabolism caused by inherited deficiencies of any of the lysosomal functions, leading to the accumulation of undegraded substrates in multiple tissues and organs. Two-third of LSDs involves the central nervous system, thus representing the most common cause of pediatric neurodegenerative diseases. Substantial progress has been made in our understanding of the pathophysiology of LSDs, leading to newly targeted therapeutic options. Enzyme replacement therapy (ERT) is currently available for seven LSDs including Gaucher disease, Fabry disease, Pompe disease, and mucopolysaccharidosis (MPS) I (Hurler disease), II (Hunter disease), IV A (Morquio A), and VI (Maroteaux–Lamy disease). ERT reduces lysosomal storage, thus slowing or sometimes avoiding progressive visceral damage altogether. However, ERT is unable to cross the blood–brain barrier (BBB), thus lacking efficacy on neurological manifestations. In patients with MPS I (Hurler disease) under 2 years of age and in selected patients with other LSD, hematopoietic stem cell transplantation is indicated. To bypass the BBB, other approaches, using small molecules are currently being tested and include substrate reduction therapy, which decreases the amount of substrate (currently available for type 1 Gaucher disease and for Niemann–Pick type C disease) and pharmacological chaperones, which enhance the residual activity of the mutant enzyme.