Fabry Disease: Current and Novel Therapeutic Strategies. A Narrative Review

Abstract

Background: Fabry disease (FD) is an inherited lysosomal storage disorder, leading to multisystemic manifestations and causing significant morbidity and mortality.

Objective: The aim of this narrative review is to present the current and novel therapeutic strategies in FD, including symptomatic and specific treatment options.

Methods: A systematic literature search was conducted to identify relevant studies, including completed and ongoing randomized-controlled clinical trials (RCTs), prospective or retrospective cohort studies, case series and case reports that provided clinical data regarding FD treatment.

Results: A multidisciplinary symptomatic treatment is recommended for FD patients, personalized according to disease manifestations and their severity. During the last two decades, FD-specific treatments, including two enzyme-replacement-therapies (agalsidase alfa and agalsidase beta) and chaperone treatment with migalastat have been approved for use and allowed for symptoms' stabilization or even disease burden reduction. More therapeutic agents are currently under investigation. Substrate reduction therapies, including lucerastat and venglustat, have shown promising results in RCTs and may be used either as monotherapy or as complementary therapy to established enzymereplacement- therapies. More stable enzyme-replacement-therapy molecules that are associated with less adverse events and lower likelihood of neutralizing antibodies formation have also been developed. Ex-vivo and in-vivo gene therapy is being tested in animal models and pilot human clinical trials, with preliminary results showing a favorable safety and efficacy profile.

Conclusion: The therapeutic landscape in FD appears to be actively expanding with more treatment options expected to become available in the near future, allowing for a more personalized approach in FD patients.

Keywords: Fabry disease; chaperone; enzyme replacement therapy; gene therapy; mutation; rare neurological diseases.

Fig. (1)

Metabolic paths targeted by Fabry Disease-specific treatments. Enzyme replacement therapy is intravenously administered, providing exogenous recombinant forms of the human α-Gal A enzyme embedded in cells via endocytosis, where they perform glycosphingolipid hydrolysis (metabolic path 1; black arrow). Corrupted or misfolded endogenous α-Gal A enzymes are repaired by chaperone treatment, allowing for sufficient glycosphingolipid hydrolysis (metabolic path 2; green arrows). Substrate reduction therapy acts by restricting the accumulation of the deficient α-Gal A byproduct (metabolic path 3; blue arrow). Ex- or in-vivo gene therapy delivers the therapeutic gene into the nuclear and endogenous α-Gal A enzyme, leading to glycosphingolipid hydrolysis (metabolic path 4; red arrows). α-Gal A: alpha-galactosidase A.