Fabry disease: Mechanism and therapeutics strategies

Abstract

Fabry disease is a monogenic disease characterized by a deficiency or loss of the α-galactosidase A (GLA). The resulting impairment in lysosomal GLA enzymatic activity leads to the pathogenic accumulation of enzymatic substrate and, consequently, the progressive appearance of clinical symptoms in target organs, including the heart, kidney, and brain. However, the mechanisms involved in Fabry disease-mediated organ damage are largely ambiguous and poorly understood, which hinders the development of therapeutic strategies for the treatment of this disorder. Although currently available clinical approaches have shown some efficiency in the treatment of Fabry disease, they all exhibit limitations that need to be overcome. In this review, we first introduce current mechanistic knowledge of Fabry disease and discuss potential therapeutic strategies for its treatment. We then systemically summarize and discuss advances in research on therapeutic approaches, including enzyme replacement therapy (ERT), gene therapy, and chaperone therapy, as well as strategies targeting subcellular compartments, such as lysosomes, the endoplasmic reticulum, and the nucleus. Finally, the future development of potential therapeutic strategies is discussed based on the results of mechanistic studies and the limitations associated with these therapeutic approaches.

Keywords: alpha-galactosidase A deficiency; fabry disease; fabry therapeutic strategies; lysosomal storage disorder; mechanistic research.

FIGURE 1

Schematic illustration of the GLA synthetic process and the various therapeutic strategies for Fabry disease.

FIGURE 2

CryoTEM imaging (A) and size distribution (B) of EV-GLA. Scale bar: 200 nm. (C) α-GLA activity test for EV-GLA. (D) Immunohistochemistry for the detection of GLA enzyme in liver tissues of GLA knockout (KO) mice after the administration of EV-GLA. Scale bar: 50 μm. (E) Measurement of α-GLA activity in the liver and kidney of various groups. (F) Measurement of Gb3 loss in various groups. (G) Gb3 immunofluorescence (green signal) in the kidneys of KO mice after the administration of a single dose of EV-GLA. Scale bar: 40 μm. Reproduced with permission (Seras-Franzoso et al., 2021). Copyright 2021, The Authors.

FIGURE 3

α-GLA activity in plasma (A) and leukocytes (B) of patients with Fabry disease following gene therapy. The plasma (C) and urine (D) levels of Gb3 in patients were altered after the initiation of gene therapy. The plasma (E) and urine (F) levels of lyso-Gb3 were altered after the initiation of gene therapy. Detection of troponin levels (G) and left ventricular mass index (LVMI) (H) in patients. Patient three did not attend all the measurements. (I) Anti-α-GLA antibody levels were assessed in five patients following viral vector-mediated therapy (Khan et al., 2021). Copyright 2021, The Authors.

FIGURE 4

α-GLA A enzymatic activity in the plasma and tissues (liver, spleen, brain, heart, kidney) of different groups and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) activity in GLA knockout (KO) mice after various treatments. NT: non-treated; SD: single dose; MD: multiple doses; Green: plasmid DNA; orange: SLP-based vector. Reproduced with permission (Rodríguez-Castejón et al., 2021). Copyright 2021, The Authors.

FIGURE 5

(A) Quantification of Gb3 concentrations in the heart and kidneys after various treatments. (B) Thin-layer chromatographic (B) and high-pressure liquid chromatographic (C) analysis of glycosphingolipid storage in wild-type (WT) and GLA knockout (KO) mice. Quantification of glycosphingolipid contents in dorsal root ganglia of KO mice with various treatments. Ctrl: control, PBS; rHSP70: rHSP70 intraperitoneal injection, 5 mg·kg⁻¹. Reproduced with permission (Kirkegaard et al., 2016). Copyright 2016, American Association for the Advancement of Science.