Treatment of Lysosomal Storage Disorders: Presence and Future

Aims: Enzyme replacement therapy is available for MPS I, II and VI, Pompe disease and Fabry disease. In addition to this therapeutic principle that is aimed to remove the accumulated storage material within the lysosome, there have been developed novel therapeutic approaches using small molecules (imino sugars) that are able to partially inhibit the substrate synthesis and influx into the catabolically compromised lysosome. This substrate reduction therapy is presently applied in patients affected by type I Gaucher disease and Niemann-Pick disease type C. Methods: Competitive inhibitors of enzymes at sub-inhibitory concentrations can act as chemical chaperones that lead to proper accurate confirmation of the mutant enzymes and thereby increase their catalytic activity. The concept of using inhibitors as chaperones has been shown to be effective in cultured cells from patients with several lysosomal storage disorders such as Pompe disease and Fabry disease. Results: In a large number of patients with a lysosomal storage disorder non-sense mutations have been identified that lead to a premature stop-codon in the transcribed mRNA and to the synthesis of a truncated and nonfunctional enzyme. And it could be demonstrated that certain low-molecular-weight drugs as for example gentamicin induced the read-through of premature stop codons, resulting in catalytic activity of the enzyme. The capability of gentamicin to suppress the stop-codon has been analysed in human MPS I fibroblasts carrying different non-sense mutations. Gentamicin treatment increased the alpha-iduronidase activity in almost all MPS I fibroblasts that were tested. Conclusion: Some limitations of therapeutic interventions are possibly due to the timing of therapy, and early treatment may be more efficient. Therefore newborn screening programmes for lysosomal storage disorder have been developed. However, as for most of these conditions a strict genotype-phenotype correlation does not exist, the screening programmes will probably not be generally introduced until the phenotype from the newborn result can be exactly predicted. Lysosomal storage disorder - treatment - enzyme replacement - substrate reduction - chaperone - read-through - newborn screening