Progress in the understanding and treatment of Fabry disease

Abstract

Background: Fabry disease is caused by α-galactosidase A deficiency. Substrates of this lysosomal enzyme accumulate, resulting in cellular dysfunction. Patients experience neuropathic pain, kidney failure, heart disease, and strokes.

Scope of review: The clinical picture and molecular features of Fabry disease are described, along with updates on disease mechanisms, animal models, and therapies.

Major conclusions: How the accumulation of α-galactosidase A substrates, mainly glycosphingolipids, leads to organ damage is incompletely understood. Enzyme replacement and chaperone therapies are clinically available to patients, while substrate reduction, mRNA-based, and gene therapies are on the horizon. Animal models exist to optimize these therapies and elucidate disease mechanisms for novel treatments.

General significance: Recent newborn screening studies demonstrate that Fabry disease is the most common lysosomal storage disease. As many countries now include Fabry disease in their screening panels, the number of identified patients is expected to increase significantly. Better knowledge of disease pathogenesis is needed to improve treatment options.

Keywords: Chaperone therapy; Enzyme replacement therapy; Fabry disease; Glycosphingolipids; Lysosomal storage disease; Rodent models.

Figure 1:. Accumulating glycosphingolipids and treatment targets in Fabry disease.

Glycosphingolipids are synthesized and degraded by sequential monosaccharide addition and removal, respectively. In Fabry disease, the lysosomal enzyme, α-Gal A, is deficient and glycosphingolipids with terminal α-galactosyl residues accumulate (red font). The major accumulating molecule is Gb3, but lyso-Gb3, Gal₂Cer, and blood group B and P1 antigens accumulate to a minor degree. Current and future therapies are aimed at replacing or promoting deficient α-Gal A activity. The FDA-approved therapies are enzyme replacement therapy and chaperone therapy. Clinical trials are currently underway to evaluate gene therapy and substrate reduction therapy. mRNA therapy is in preclinical development. Substrate reduction therapy trials are currently evaluating inhibitors of GlcCer synthase, which catalyzes a biosynthetic reaction prior to formation of Gb3, thereby reducing overall Gb3 load. However, this therapeutic strategy also inhibits the formation of GlcCer and LacCer, glycosphingolipids key to critical cellular processes, which ultimately results in an unfavorable side effect profile. Further, substrate reduction therapy inhibits the formation of other glycosphingolipids, such as gangliosides. Specific inhibition of Gb3 synthase may be more tolerable to patients with Fabry disease, but this approach is conceptual and remains to be developed and tested. The –R group represents that the B antigen glycan can be conjugated to either a protein or lipid. Abbreviations: globotetraosylceramide (Gb4), globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3), lactosylceramide (LacCer), glucosylceramide (GlcCer), ceramide (Cer), galactosylceramide (GalCer), digalactosylceramide (Gal₂Cer), α-galactosidase A (α-Gal A), glucosylceramide synthase (GlcCer synthase).

Figure 2:. Cellular mechanisms of Fabry disease pathogenesis.

A pathogenic genetic mutation in the gene encoding α-Gal A causes decreased activity of this lysosomal enzyme. Subsequently α-Gal A substrates accumulate and lead to cellular dysfunction through multiple pathways. Substrate accumulation has been shown to alter the normal function of several subcellular components that are listed along with the corresponding effects observed in studies involving cells^c, Fabry patients^p, Fabry mice^m, and Fabry rats^r.