Treating lysosomal storage diseases with pharmacological chaperones: from concept to clinics

Abstract

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.

Figure 1. Therapeutic approaches for LSDs

Till the end of the 1980s, only support therapies were available for LSD patients. During the past two decades, different therapeutic approaches have been introduced, including HSCT, ERT, PCT and SRT. Each of these approaches has been applied to different diseases. HSCT has been applied to several LSDs, not indicated in the figure (for a review, see Orchard et al, 2007). The year of the first reports on clinical applications of each therapy is indicated. ERT is now under development for several LSDs. EET has been translated for Fabry disease. Two studies on PCT for Gaucher and Pompe disease are in progress, but the results are not yet published. Although gene therapy pilot studies have been conducted (Worgall et al, 2008) or are in preparation, it is currently difficult to predict when their clinical translation will take place in this area.

Figure 2. Effect of pharmacological chaperones on misfolded lysosomal enzymes

1. Folding of lysosomal enzymes is assisted by endogenous molecular chaperones. While wild type enzymes are properly folded by the chaperones and correctly transported to their destination (green arrows), mutated enzymes fail to fold efficiently into their native conformation, and are retro-translocated into the cytosol and degraded by the ERAD machinery (red arrows).

2. Pharmacological chaperones favour the folding of mutated enzymes that retain their catalytic activity, and prevent their recognition by the quality control system. The complex chaperone-mutated enzyme is delivered, at least partially, to the lysosomal compartment, where the chaperone is displaced from the active site of the enzyme by the excess natural substrate.

Figure 3. Synergy of ERT and chaperones

The enhancing effects of chaperones may take place at different levels.

1. By improving the uptake of the recombinant enzymes by mutant cells,

2. Favouring their intracellular trafficking to lysosomes and

3. Increasing the enzyme's stability. Improved lysosomal trafficking is an important therapeutic goal, as these organelles are the site of substrate storage and because in the late endosomal/lysosomal compartment enzymes are processed into the mature and active isoforms. Increased stability may result in sustained corrective levels of intracellular enzymes.