Treatment of Fabry Disease: Established and Emerging Therapies

Abstract

Fabry disease (FD) is a rare, X-linked inherited disorder of glycosphingolipid metabolism. It leads to the progressive accumulation of globotriaosylceramide within lysosomes due to a deficiency of α-galactosidase A enzyme. It involves multiple organs, predominantly the renal, cardiac, and cerebrovascular systems. Early diagnosis and treatment are critical to prevent progression to irreversible tissue damage and organ failure, and to halt life-threatening complications that can significantly reduce life expectancy. This review will focus on the established and emerging treatment options for FD.

Keywords: Fabry disease; chaperone therapy; enzyme replacement therapy; gene therapy; left ventricular hypertrophy.

Figure 1

Overview of the ceramide pathway and therapeutic targets. ERT replaces deficient endogenous enzyme with recombinant enzyme (Agalsidase-α or Agalsidase-β). Chaperone (migalastat) binds reversibly to and stabilizes amenable gene variants of α-GAL, thereby facilitating proper trafficking of the enzyme to lysosomes and increasing enzyme activity. Substrate reduction therapy (lucerastat or venglustat) causes inhibition of glucosylceramide synthesis and reduces the accumulation of glycosphingolipids, including glucosylceramide and globotriaosylceramide (GL3).

Figure 2

The basic requisites of effective gene therapy include a transcription promoter that is active in affected tissues and optimized for high gene expression. Other essential components include the stabilization of mRNA and inhibiting viral replication.

Figure 3

Overview of the gene therapy techniques being used in trials for FD treatment. The first step is to mobilize hematopoietic stem/progenitor cells (HSPCs) and integrate GLA cDNA into host DNA using lentivirus (LV). These transduced HSPCs are transplanted back into bone marrow for α-galactosidase A (α-GAL) expression. Adeno-associated virus (AAV) or adenovirus can also be used for GLA cDNA transfer into target cells. Lipid nanoparticle encapsulated mRNA encoding human GLA is another safe method of endogenous α-GAL expression.