Developments in the treatment of Fabry disease

Abstract

Enzyme replacement therapy (ERT) with recombinant α-galactosidase A (r-αGAL A) for the treatment of Fabry disease has been available for over 15 years. Long-term treatment may slow down disease progression, but cardiac, renal, and cerebral complications still develop in most patients. In addition, lifelong intravenous treatment is burdensome. Therefore, several new treatment approaches have been explored over the past decade. Chaperone therapy (Migalastat; 1-deoxygalactonojirimycin) is the only other currently approved therapy for Fabry disease. This oral small molecule aims to improve enzyme activity of mutated α-galactosidase A and can only be used in patients with specific mutations. Treatments currently under evaluation in (pre)clinical trials are second generation enzyme replacement therapies (Pegunigalsidase-alfa, Moss-aGal), substrate reduction therapies (Venglustat and Lucerastat), mRNA- and gene-based therapy. This review summarises the knowledge on currently available and potential future options for the treatment of Fabry disease.

Keywords: Fabry disease; chaperone therapy; enzyme replacement therapy (ERT); gene therapy; substrate reduction therapy (SRT); treatment.

Figure 1

Overview of different approaches in treating Fabry disease; Enzyme replacement therapy (ERT) aims to restitute defective αGAL A. Chaperones bind to the active site of the unstable αGAL A to aid proper folding. Substrate reduction therapy targets the glycosphingolipid synthesis to reduce formation of Gb3 and its derivatives. Gene therapy aims to correct the underlying genetic defect of FD. MRNA therapy induces transient endogenous αGAL A production. The egress of Gb3 can potentially be stimulated by enhancing cholesterol efflux (Figure 4). FD, Fabry disease

Figure 2

Similarities and differences in chemical structures of different iminosugars (both chaperone and substrate reduction therapy)

Figure 3

Glycosphingolipids pathways and location of intervention of substrate reduction therapy and chaperone therapy preparations. Dashed arrow indicates the mutated enzyme in FD. GM 1, 2, and 3 are gangliosides. Arrows indicate specific enzymatic reactions. Stop signs indicate point of intervention for each iminosugar. Red arrow indicates accumulation. *Migalastat inhibits αGAL A in high doses but aids proper folding of unstable αGAL A, resulting from certain amenable mutations, thus increasing enzymatic activity. FD, Fabry disease

Figure 4

Hypothesized method of altered lipid homeostasis in Fabry disease. 1. Gb3 and cholesterol are taken up through the LDL receptor.102, 103, 104 2. Gb3 is mistargeted to lysosomes instead of Golgi and other membranes.105, 106, 107 3. Gb3 causes inhibition of ApoA1 mediated efflux of cholesterol.108 4. Storage of GSLs causes upregulation of the LDL receptor thus increasing intracellular uptake of cholesterol and additional GSLs.105, 106, 107 5. Increased uptake, mistargeting, and decreased efflux results in lysosomal accumulation of lipids. GSLs, glycosphingolipids; LDL, low‐density lipoprotein