Abstract
Fabry disease (FD) is a lysosomal storage disorder caused by mutations of the GLA gene that lead to a deficiency of the enzymatic activity of α-galactosidase A. Available therapies for FD include enzyme replacement therapy (ERT) (agalsidase alfa and agalsidase beta) and the chaperone migalastat. Despite the large body of literature published about ERT over the years, many issues remain unresolved, such as the optimal dose, the best timing to start therapy, and the clinical impact of anti-drug antibodies. Migalastat was recently approved for FD patients with amenable GLA mutations; however, recent studies have raised concerns that “in vitro” amenability may not always reflect “in vivo” amenability, and some findings on real-life studies have contrasted with the results of the pivotal clinical trials. Moreover, both FD specific therapies present limitations, and the attempt to correct the enzymatic deficiency, either by enzyme exogenous administration or enzyme stabilization with a chaperone, has not shown to be able to fully revert FD pathology and clinical manifestations. Therefore, several new therapies are under research, including new forms of ERT, substrate reduction therapy, mRNA therapy, and gene therapy. In this review, we provide an overview of the state-of-the-art on the currently approved and emerging new therapies for adult patients with FD.
Highlights
Fabry disease (FD) (OMIM 301500) is a rare X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to deficiency of the enzymatic activity of α-galactosidase A
Another study showed that 19.4% of patients on agalsidase alfa 0.2 mg/Kg and 13.3% of patients on agalsidase beta 1 mg/Kg progressed, during the 59-month study duration, to a composite clinical endpoint consisting of renal events, cardiovascular events, cerebrovascular events (TIA or stroke documented by a physician or acute hearing loss), or death
The dose reduction of agalsidase beta from 1 mg/Kg eow to 0.5 mg/Kg per month for 1 year led to a significant increase of plasma lyso-GB3 in males, but no differences were seen on clinical events, Mainz Severity Score Index (MSSI), pain, estimated glomerular filtration rate (eGFR), or left ventricular (LV) mass [66]
Summary
Fabry disease (FD) (OMIM 301500) is a rare X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to deficiency of the enzymatic activity of α-galactosidase A. Agalsidase alfa has been demonstrated to decrease plasma GB3 [14,15,16] and lyso-GB3 [17] and urinary GB3 [14,16] levels; to decrease GB3 deposits in kidney endothelial cells [15]; to slow the decline of the estimated glomerular filtration rate (eGFR) [15,16]; to reduce/stabilize left ventricular (LV) mass [14,18,19] and wall thickness [19]; to improve/stabilize vestibular/auditory symptoms [20,21]; to improve nerve sensitivity [22], gastrointestinal symptoms [23], sweat function [23], pain [15], and pain-related quality of life [15]. EGFR, estimated glomerular filtration rate; ER, endoplasmic reticulum; IAR, infusion associated reactions; LV, left ventricular; mGFR, measured glomerular filtration rate
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