Small Molecules: Substrate Inhibitors, Chaperones, Stop-Codon Read Through, and Beyond

Abstract Lysosomal storage disorders are rare genetic disorders due to deficient lysosomal activity, which leads to progressive accumulation of nonmetabolized substrates. Patient's clinical outcomes have significantly improved since the advent of enzyme replacement therapy, even though this therapeutic approach presents important limitations, such as immune reactions, low bioavailability of recombinant enzymes, and incapability to reach the central nervous system. New strategies based on gene therapy or small molecules have been proposed and tested as an alternative to enzyme replacement therapy or to complement it. Small molecules are orally administrated, no antigenic compound that can diffuse across cell membranes and distribute in steady-state concentrations, also reaching the central nervous system. Substrate reduction therapy, pharmacological chaperones, and stop-codon read-through enhancers are small molecules currently available for the treatment of lysosomal storage disorders. This article describes the characteristics of this class of compounds and the possible strategies to improve their efficiency in future development.

Substrate reduction therapy as a new treatment option for patients with Gaucher disease type 1: A review of literatures

Gaucher disease type 1 (GD1) is an inherited lysosomal storage disorder caused by deficiency of acid β-glucosidase. The diminished enzyme activity leads to the accumulation of substrates and results in multi-systemic manifestations including hepatosplenomegaly, anemia, thrombocytopenia, and bone diseases. Enzyme replacement therapy (ERT) by infusion of recombinant protein has been the standard treatment for over 20 years. Despite the successful long-term treatment with ERT, several unmet needs remain in the treatment of GD1 such as severe pulmonary and skeletal manifestations. Substrate reduction therapy (SRT) reduces the accumulation of substrates by inhibiting their biosynthesis. Eliglustat, a new oral SRT, was approved in United States and Europe as a first-line therapy for treating adult patients with GD1 who have compatible CYP2D6 metabolism phenotypes. Although eliglustat is not yet available in Korea, introduction and summary of this new treatment modality are provided in this paper by review of literatures. Despite the fact that there are only limited studies to draw resolute conclusions, the current data demonstrated that eliglustat is not inferior to ERT in terms of its clinical efficacy. The approval of eligustat enables eligible adult GD1 patients to have the option of oral therapy although it still needs further studies on long-term outcomes. The individual patient should be assessed carefully for the choice of treatment modality when eliglustat becomes available in Korea. Furthermore, the clinical guidelines for Korean patients with GD1 regarding the use of eliglustat needs to be developed in near future.