Fabry Disease: An Updated Perspective and Review of Treatment and Therapies

Abstract

Fabry disease (FD) is a progressive, multisystemic, X-linked lysosomal storage disorder that when untreated leads to decreased quality of life, chronic pain, and end organ disease; however, advances in therapy have significantly altered its original natural history. This paper briefly reviews the pathophysiology and clinical features of FD before focusing on current and future treatments. Enzyme replacement therapy (ERT) and pharmacologic chaperone therapy are established treatments with long-term data showing disease stabilization and improved outcomes when the therapies are initiated prior to end organ damage. Even with the modified FD phenotype facilitated by the approved therapies, there are still gaps in treatment and a need for new and adjunctive therapies. Some of these gaps may be addressed by emerging therapies in clinical trials such as oral substrate reduction therapies, second-generation ERTs, and gene therapies. Early clinical trials of gene therapy have had mixed results; however, a few have good safety and efficacy profiles and at least one is moving to regulatory review. Additional preclinical work in alternative delivery mechanisms, reduction of inflammatory response, and small molecules are reviewed as future directions that may help close additional therapeutic gaps. These therapeutic developments target a more personalized and effective approach to FD potentially improving adherence, outcomes, and quality of life.