Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Enzyme reconstitution/replacement therapy for lysosomal storage diseases T. Andrew Burrow, Robert J. Hopkin, Nancy D. Leslie, Bradley T. Tinkle and Gregory A. Grabowski Purpose of review Over the past 15 years, the lysosomal storage diseases have become paradigms for the specific treatment of monogenic disorders, particularly those affecting children. This review summarizes the phenotypes and recent literature regarding enzyme reconstitution (replacement) therapy and outcomes for such treatable lysosomal storage diseases: Gaucher disease, Fabry disease, Pompe disease and the mucopolysaccharidoses. Recent findings Recent clinical trials have shown that enzyme reconstitution therapy effectively treats many of the manifestations of the lysosomal storage diseases. When initiated early in the disease course, enzyme reconstitution therapy can reverse some disease manifestations, but may not completely alleviate the disease progression. Enzyme reconstitution therapy is generally well tolerated. Many adverse events are antibody-related, but can be managed without requiring cessation of enzyme reconstitution therapy. Documented IgE reactions, i.e. anaphylactoid, are quite rare (fewer than 1%). Summary Enzyme reconstitution therapy is a safe and effective treatment modality available for several of the lysosomal storage diseases. Owing to the short history of enzyme reconstitution therapy, the long-term outcomes of enzyme reconstitution therapy-treated individuals are unknown and require further investigation. Medical professionals must learn to identify patients likely to benefit from these life-changing therapies so as to prevent many of the devastating, irreversible complications of the lysosomal storage diseases. Keywords Fabry disease, Gaucher disease, glycosphingolipids, lysosomes, mucopolysaccharidoses, Pompe disease Curr Opin Pediatr 19:628–635. ß 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins. Division of Human Genetics, Cincinnati Children’s Hospital Medical Center and the Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA Correspondence to Gregory A. Grabowski, MD, Cincinnati Children’s Hospital Medical Center, Division of Human Genetics, 3333 Burnet Avenue, MLC 4006, Cincinnati, OH 45229-3039, USA Tel: +1 513 636 7290; fax: +1 513 636 2261; e-mail: greg.grabowski@cchmc.org Current Opinion in Pediatrics 2007, 19:628–635 Abbreviations BMT bone marrow transplantation CNS central nervous system ERT enzyme reconstitution therapy FDA Food and Drug Administration GAA acid a-glucosidase GAG glycosaminoglycan GL3 globotriaosylceramide LSD lysosomal storage disease MPS mucopolysaccharidosis ß 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins 1040-8703 Introduction Over the past 15 years, the lysosomal storage diseases (LSDs) have become paradigms for specific treatment of monogenic disorders, particularly those affecting chil- dren. Except for Fabry disease and Hunter syndrome [mucopolysaccharidosis (MPS) II] that are X-linked, the other around 40 LSDs are autosomal recessive traits. For currently treatable LSDs, a single gene is disrupted by various mutations (single substitutions to gene deletions) that lead to a defective encoded enzyme protein and/or activity. Lysosomal enzymes are synthesized on the rough endoplasmic reticulum, posttranslationally pro- cessed in the Golgi and targeted to the lysosomes [1]. The majority of such enzymes require the mannose-6- phosphate receptor system to direct newly synthesized or exogenously supplied enzymes to the lysosome; the Gaucher disease enzyme does not use this system. Other receptors (e.g. the mannose receptor) act as Trojan horses to deliver enzymes into lysosomes of cells. The LSDs lack sufficient enzyme activity to prevent pathologic cellular accumulation of specific macromolecules, i.e. glycosphingolipids, mucopolysaccharides or glycogen, that disrupt cell functions and perpetuate the disease by poorly defined mechanisms. Clinical phenotypes within each LSD range from very severe infantile to attentuated variants in adolescence to adulthood. The nature of the mutation affects the amount of enzyme activity and is a major determinant of the phenotypes, i.e. the threshold hypothesis that small incremental changes in enzyme function in specific tis- sues lead to large variations in clinical course [2]. Many visceral tissues are accessible to intravenously supplied enzymes, whereas the brain is not. 628