Contemporary therapeutics and new drug developments for treatment of Fabry disease: a narrative review

Abstract

Fabry disease (OMIM 301500) is an X-linked (Xq22.1) lysosomal storage disorder leading to a progressive multisystem disease with high variability in both genotype and phenotype expression. The pathophysiological origin is found in an enzyme deficiency of the α-galactosidase A (enzyme commission no. 3.2.1.22) leading to accumulation of globotriaosylceramides in all lysosome carrying tissue. Especially organ manifestations of the heart, kidneys and nervous system are of significant prognostic value and might complicate with Fabry-associated pain, young aged cryptogenic stroke, proteinuria, kidney failure, hypertrophic cardiomyopathy, heart failure, malign cardiac rhythm disturbances and eventually sudden cardiac death. Up to the introduction of the first enzyme replacement agent in 2001, patients faced the disease's natural course with no disease-specific therapies available. Today, two recombinant enzyme replacement agents (Fabrazyme^®, Sanofi Genzyme, Cambridge, MA, USA; Replagal^®, Takeda Pharmaceutical, Tokio, Japan) and one oral chaperone therapy (Migalastat^®, Amicus Therapeutics, USA) are available and well-established in daily clinical practice. Substrate reduction therapy, second-generation enzyme replacement agents and different gene therapy approaches are currently undergoing preclinical and clinical trial phases and aim to improve therapeutic success and long-term outcome of patients with Fabry disease. This narrative review summarizes the currently available therapeutic options and future perspectives in Fabry disease.

Keywords: Fabry disease; chaperone therapy; enzyme replacement therapy; gene therapy; substrate reduction therapy.