Enzyme Replacement Therapy for Lysosomal Storage Disorders

Enzyme replacement therapy (ERT) has transformed the management of several lysosomal storage disorders by supplying patients with functional versions of the deficient hydrolases that accumulate specific substrates within the lysosome. First approved for Gaucher disease two decades ago, ERT has since been extended to Fabry disease, Pompe disease and other rare syndromes characterised by pathogenic lipid or glycoprotein storage. Intravenous infusions of recombinant enzymes restore lysosomal degradation capacity in macrophages, hepatocytes, endothelial cells and other target tissues, leading to substrate clearance, amelioration of organomegaly and improvements in quality of life. However, ERT faces ongoing challenges including limited biodistribution to skeletal muscle and the central nervous system, infusion‐related immune responses, high cost and the necessity for lifelong regular administration. Advances in formulation, dosing regimens and co-therapies aim to enhance tissue uptake, prolong enzyme half-life and reduce immunogenicity. Moreover, ERT has revealed insights into disease biology, indicating that substrate reduction alone may be insufficient to reverse established fibrosis or neurodegeneration. These developments have spurred the exploration of adjunctive approaches such as pharmacological chaperones, substrate reduction therapy and gene‐based delivery, with the goal of achieving more durable correction of lysosomal function and improved clinical outcomes worldwide.

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Enzyme Replacement Therapy for Lysosomal Storage Disorders publication trend

The graph below shows the total number of articles in enzyme replacement therapy for lysosomal storage disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Lysosomal storage disorder: A genetic condition in which deficient lysosomal enzymes lead to accumulation of undegraded substrates within cells.

Enzyme replacement therapy (ERT): The intravenous administration of recombinant enzymes to restore deficient lysosomal activity.

Lysosome: A membrane-bound organelle containing hydrolytic enzymes responsible for intracellular degradation of macromolecules.

Substrate reduction therapy: A pharmacological approach that lowers the synthesis of the accumulated substrate to balance residual enzyme activity.

Pharmacological chaperone: A small molecule that binds and stabilises a misfolded enzyme, facilitating its proper trafficking to the lysosome.

Podocyte: A specialised epithelial cell in the kidney glomerulus that supports filtration and is vulnerable to substrate overload.

References

1. Synuclein α accumulation mediates podocyte injury in Fabry nephropathy. Journal of Clinical Investigation (2023).
2. The effect of enzyme replacement therapy on clinical outcomes in male patients with Fabry disease: A systematic literature review by a European panel of experts. Molecular Genetics and Metabolism Reports (2019).
3. Gaucher Disease in Bone: From Pathophysiology to Practice. Journal of Bone and Mineral Research (2019).