substratereduction

Substrate reduction, also called substrate-reduction therapy (SRT), is a pharmacological strategy that aims to decrease the synthesis of substrates that accumulate in cells due to enzyme deficiencies or transport defects. In lysosomal storage disorders, SRT reduces the substrate burden within lysosomes, often used to complement enzyme replacement therapies and other treatment approaches.

Mechanistically, SRT works by inhibiting specific steps in biosynthetic pathways that produce the accumulating substrate. A common target is glucosylceramide synthase (UGCG), which lowers the production of glucosylceramide and thereby reduces downstream storage of glycolipids in cells.

Representative examples and use cases include oral agents such as miglustat and eliglustat that inhibit UGCG. These drugs have been employed primarily in Gaucher disease type 1 as alternatives or adjuncts to enzyme replacement therapy, and research has explored their use in other lysosomal storage diseases with varying regulatory approvals by country. SRT may be considered when enzyme replacement is unsuitable or when non-invasive, oral therapy is preferred; its applicability depends on disease type, tissue involvement, and access to approved indications.

Limitations and considerations include variable efficacy across diseases and tissues, with central nervous system outcomes often limited by the blood–brain barrier. Side effects can include gastrointestinal symptoms, weight loss, and tremor, and some agents have drug interaction considerations or require pharmacogenetic or metabolic monitoring. Ongoing research seeks to expand indications, optimize targeting, and compare SRT with alternative treatment modalities.