Lysosomal storage diseases are a group of rare, inborn, metabolic errors characterized by deficiencies in normal lysosomal function and by intralysosomal accumulation of undegraded substrates. The past 25 years have been characterized by remarkable progress in the treatment of these diseases and by the development of multiple therapeutic approaches. These approaches include strategies aimed at increasing the residual activity of a missing enzyme (enzyme replacement therapy, hematopoietic stem cell transplantation, pharmacological chaperone therapy and gene therapy) and approaches based on reducing the flux of substrates to lysosomes. As knowledge has improved about the pathophysiology of lysosomal storage diseases, novel targets for therapy have been identified, and innovative treatment approaches are being developed.

Lysosomal storage diseases are a group of metabolic disorders caused by deficiencies of several components of lysosomal function. Most commonly affected are lysosomal hydrolases, which are involved in the breakdown and recycling of a variety of complex molecules and cellular structures. The understanding of lysosomal biology has progressively improved over time. Lysosomes are no longer viewed as organelles exclusively involved in catabolic pathways, but rather as highly dynamic elements of the autophagic‐lysosomal pathway, involved in multiple cellular functions, including signaling, and able to adapt to environmental stimuli. This refined vision of lysosomes has substantially impacted on our understanding of the pathophysiology of lysosomal disorders. It is now clear that substrate accumulation triggers complex pathogenetic cascades that are responsible for disease pathology, such as aberrant vesicle trafficking, impairment of autophagy, dysregulation of signaling pathways, abnormalities of calcium homeostasis, and mitochondrial dysfunction. Novel technologies, in most cases based on high‐throughput approaches, have significantly contributed to the characterization of lysosomal biology or lysosomal dysfunction and have the potential to facilitate diagnostic processes, and to enable the identification of new therapeutic targets.

Lysosomal storage diseases (LSDs) are a group of genetic disorders due to defects in any aspect of lysosomal biology. During the past two decades, different approaches have been introduced for the treatment of these conditions. Among them, enzyme replacement therapy (ERT) represented a major advance and is used successfully in the treatment of some of these disorders. However, ERT has limitations such as insufficient biodistribution of recombinant enzymes and high costs. An emerging strategy for the treatment of LSDs is pharmacological chaperone therapy (PCT), based on the use of chaperone molecules that assist the folding of mutated enzymes and improve their stability and lysosomal trafficking. After proof‐of‐concept studies, PCT is now being translated into clinical applications for Fabry, Gaucher and Pompe disease. This approach, however, can only be applied to patients carrying chaperone‐responsive mutations. The recent demonstration of a synergistic effect of chaperones and ERT expands the applications of PCT and prompts a re‐evaluation of their therapeutic use and potential. This review discusses the strengths and drawbacks of the potential therapies available for LSDs and proposes that future research should be directed towards the development of treatment protocols based on the combination of different therapies to improve the clinical outcome of LSD patients.

Lysosomal storage disorders (LSDs) are a group of inborn metabolic diseases caused by mutations in genes that encode proteins involved in different lysosomal functions, in most instances acidic hydrolases. Different therapeutic approaches have been developed to treat these disorders. Pharmacological chaperone therapy (PCT) is an emerging approach based on small-molecule ligands that selectively bind and stabilize mutant enzymes, increase their cellular levels, and improve lysosomal trafficking and activity. Compared to other approaches, PCT shows advantages, particularly in terms of oral administration, broad biodistribution, and positive impact on patients' quality of life. After preclinical in vitro and in vivo studies, PCT is now being translated in the first clinical trials, either as monotherapy or in combination with enzyme replacement therapy, for some of the most prevalent LSDs. For some LSDs, the results of the first clinical trials are encouraging and warrant further development. Future research in the field of PCT will be directed toward the identification of novel chaperones, including new allosteric drugs, and the exploitation of synergies between chaperone treatment and other therapeutic approaches.

In spite of the progress in the treatment of lysosomal storage diseases (LSDs), in some of these disorders the available therapies show limited efficacy and a need exists to identify novel therapeutic strategies. We studied the combination of enzyme replacement and enzyme enhancement by pharmacological chaperones in Pompe disease (PD), a metabolic myopathy caused by the deficiency of the lysosomal acid α-glucosidase. We showed that coincubation of Pompe fibroblasts with recombinant human α-glucosidase and the chaperone N-butyldeoxynojirimycin (NB-DNJ) resulted in more efficient correction of enzyme activity. The chaperone improved α-glucosidase delivery to lysosomes, enhanced enzyme maturation, and increased enzyme stability. Improved enzyme correction was also found in vivo in a mouse model of PD treated with coadministration of single infusions of recombinant human α-glucosidase and oral NB-DNJ. The enhancing effect of chaperones on recombinant enzymes was also observed in fibroblasts from another lysosomal disease, Fabry disease, treated with recombinant α-galactosidase A and the specific chaperone 1-deoxygalactonojirimycin (DGJ). These results have important clinical implications, as they demonstrate synergy between pharmacological chaperones and enzyme replacement. A synergistic effect of these treatments may result particularly useful in patients responding poorly to therapy and in tissues in which sufficient enzyme levels are difficult to obtain.

The recent advancements in the knowledge of lysosomal biology and function have translated into an improved understanding of the pathophysiology of mucopolysaccharidoses (MPSs). The concept that MPS manifestations are direct consequences of lysosomal engorgement with undegraded glycosaminoglycans (GAGs) has been challenged by new information on the multiple biological roles of GAGs and by a new vision of the lysosome as a signaling hub involved in many critical cellular functions. MPS pathophysiology is now seen as the result of a complex cascade of secondary events that lead to dysfunction of several cellular processes and pathways, such as abnormal composition of membranes and its impact on vesicle fusion and trafficking; secondary storage of substrates; impairment of autophagy; impaired mitochondrial function and oxidative stress; dysregulation of signaling pathways. The characterization of this cascade of secondary cellular events is critical to better understand the pathophysiology of MPS clinical manifestations. In addition, some of these pathways may represent novel therapeutic targets and allow for the development of new therapies for these disorders.