Pharmacological small molecules for the treatment of lysosomal storage disorders

Importance of the field: Inherited lysosomal storage diseases often cause severe disability and have a devastating effect on quality of life. Enzyme replacement therapy (ERT) forms a cornerstone in the treatment of lysosomal enzyme deficiencies. Although for some lysosomal disorders ERT is lifesaving, important intrinsic restrictions of the approach are limited access of infused enzyme to less accessible body compartments such as theCNS, the burden of frequent intravenous administration, the emergence of antibodies and the high associated costs. Pharmacological small molecules may overcome these limitations. Areas covered in this review: Several novel therapeutic approaches using small molecules are emerging: substrate reduction therapy, pharmacological chaperone therapy, premature nonsense mutation suppressors and proteostasis regulators. What the reader will gain: Based on an extensive literature search up until June 2010, we here review the various therapeutic approaches with small compounds, including those currently in clinical use and those that have entered clinical trials. Compounds that are still in the preclinical phase are also briefly discussed. Take home message: pharmacological small molecules are a new class of agents that show great promise for the treatment of lysosomal storage disorders.