Enzyme replacement therapy: lessons learned and emerging questions

Introduction: Over the past two decades, enzyme therapy for lysosomal storage disorders (LSDs) has become integral to the specific treatment paradigms of monogenic disorders. As enzyme replacement therapy (ERT) has been successfully introduced for patients with Gaucher disease type 1, this treatment principle has been taken into consideration for other LSDs as well. However, repeating this spectacular success in the mucopolysaccharidoses and Fabry or Pompe disease proved to be impossible.Areas covered: This article is an overview of lessons learned during the last 20 years since ERT was first introduced. It highlights some emerging questions and potential reasons why ERT has not been as universally successful as hoped.Expert opinion: The usefulness of ERT is limited due to the fact that it does not have beneficial effects on all aspects of a disorder to the same degree. Even with an early introduction of treatment there are still several limitations of this therapy: delivering therapeutic levels of lysosomal enzymes across the blood–brain barrier or effect on dysostosis multiplex, joint disease or cardiac valve disease. In fact, despite efforts, ERT mostly slows down disease progression and attenuates symptom expression.