Abstract

Enzyme replacement therapy (ERT) has represented a major therapeutic breakthrough for lysosomal storage diseases (LSDs) over the past three decades, translating fundamental insights into lysosomal enzyme trafficking and cross-correction into effective clinical interventions. Since its first application in Gaucher disease, ERT has been extended to multiple LSDs, leading to substantial improvements in survival, organ function, and quality of life. However, accumulated long-term clinical experience has revealed several important limitations that preclude ERT from being universally effective.

This review discusses key factors influencing the efficacy of ERT, including enzyme biodistribution, receptor-mediated uptake, pharmacokinetics, and the impact of physiological barriers such as the blood–brain barrier. Tissue-specific variability in response, immune reactions, and the influence of disease stage and secondary pathogenic mechanisms are examined as major determinants of therapeutic outcome. In addition, challenges related to manufacturing, cost, and treatment burden are considered.

Advances in biotechnology have led to the development of second- and third-generation enzymes with improved targeting properties, reduced immunogenicity, and enhanced stability. Novel approaches, including glycoengineering, chimeric enzymes capable of crossing biological barriers, nanoparticle-based delivery systems, and alternative production platforms such as plant-based expression systems, are expanding the therapeutic landscape. At the same time, emerging strategies aimed at modulating immune responses and optimizing treatment protocols are contributing to improved clinical management.

Finally, the evolving role of ERT is discussed in the context of emerging therapies, particularly gene therapy. While gene-based approaches hold great promise, ERT is likely to remain an essential component of treatment, as a complementary strategy or a bridge to more definitive therapies. Lessons learned from decades of clinical use provide a foundation for future innovations aimed at overcoming current limitations and improving outcomes.