Emerging drugs for lysosomal storage diseases

Abstract

Importance of the field: Because orphan drug regulations encouraged development of drugs for rare disorders by granting marketing exclusivity for many years and other commercial benefits, treatment has become achievable for a few lysosomal storage disorders also. The presently available therapies, however, are not able to address all aspects of these multisystemic disorders and do not cure the patient. Therefore, there is a need for producing new drugs that are based on known pathophysiological mechanisms, such as enzyme replacement or inhibition of substrate synthesis, or which use new approaches to prevent the build-up of storage material.Areas covered in this review: New compounds that are being designed by different pharmaceutical companies can be divided in two groups, enzyme targeted and substrate targeted drugs. Enzyme targeted drugs include substances that modify the enzyme to make it more accessible to organs such as the bone or the brain, enhance enzyme activity (chaperones) or activate enzyme synthesis by small molecules that induce read-through of premature stop codons of genes that bear a nonsense mutation. To the group of substrate targeted drugs belong substances that inhibit the synthesis or modify the structure of the substrate (substrate deprivation or substrate optimization, respectively). For this review, a literature research has been undertaken that covers the years 1968 – 2010.What the reader will gain: The reader of this paper will get an overview of drugs for lysosomal storage disorders that are on the market or are under development. This will help in the understanding of the pathophysiological mechanisms that underlie these rare metabolic diseases. In addition, the reader should realize that the increasing number of these very expensive drugs may lead to significant consequences for the health economic system.Take home message: In the last years, the interest of scientists and pharmaceutical companies in lysosomal storage disorders has increased dramatically, leading to the production of a rising number of different drugs. These drugs act at several stages of the pathophysiological cascade, for example, at the level of the substrate (substrate deprivation) or of the enzyme (enzyme enhancement). The presently available treatments are not able to address all clinical manifestations of these disorders, and it will still take a long time until new drugs are developed that are capable of curing the patients.