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 enzyme-replacement-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.

Author Response: D313Y Variant in Fabry Disease: A Systematic Review and Meta-analysis

“…We thank Lackova et al for their comments on our systematic review and meta-analysis regarding D313Y -variation in Fabry disease (FD) and for presenting their interesting findings. 1,2 Although parkinsonism is not considered a typical FD manifestation, 3 the reported prevalence of D313Y variant in this single-center cohort of patients with Parkinson disease was higher compared with the general population. 2 Furthermore, misdiagnosis of multiple sclerosis (MS) in patients with an ultimate FD diagnosis has been previously reported, mandating the consideration of FD during differential diagnosis for MS, especially when atypical multisystemic findings or positive family history exists.…”

Impaired cerebral autoregulation in Fabry disease: A case‐control study

“…8 With regard to the FD-specific treatment, enzyme replacement therapy (ERT) and chaperone treatment are currently available. 4 In the case of ERT and its effect on leukoencephalopathy, contradictory results are reported in the literature, with a phase IV, randomized, controlled clinical trial with a limited sample size (n = 41) showing a significant association of treatment with stabilization of white matter lesions, 8 whereas a larger (n = 149), yet observational, study disputing the relationship between treatment and the progression rate of white matter hyperintensities. 45 Indeed, ERT-large molecules cannot cross the blood-brain barrier and, therefore, may not have a clear effect on leukoencephalopathy.…”

“…45 Indeed, ERT-large molecules cannot cross the blood-brain barrier and, therefore, may not have a clear effect on leukoencephalopathy. 4,45 On the other hand, chaperone treatment is based on the administration of small molecules, which can stabilize the endogenous enzyme of FD patients, increase its enzymatic function, and can also cross the blood-brain barrier. 46,47 In that way, chaperone treatment may have the theoretical potential to reduce the occurrence of both white matter lesions and cerebrovascular events.…”

“…Management and treatment of FD patients were based on current recommendations and best clinical practice provided by a multidisciplinary team with experience in rare diseases. 4,16…”

“…It is characterized by the deficiency or dysfunction of the enzyme alpha‐galactosidase A, resulting in the accumulation of glycosphingolipids in the lysosomes of various organs 1 . The classic phenotype of FD is characterized by clinical manifestations of the heart, kidney, skin, eyes, and central and peripheral nervous system 3,4 . With regard to the central nervous system (CNS), glycosphingolipids may accumulate in the endothelium, causing vascular complications, such as stroke in FD patients 5 .…”