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Giliberti et al. J Transl Genet Genom 2024;8:340-54 https://dx.doi.org/10.20517/jtgg.2024.41 Page 342

[17]
conformational maturation, glycosylation, and distribution of α-GAL A in cells .

Finally, in vitro studies have explored strategies to reduce intra-lysosomal storage by enhancing the efflux of
stored substances from the lysosomal vesicle and facilitating its subsequent expulsion from the cell [18,19]
[Figure 1].

This review aims to comprehensively evaluate all current and emerging therapeutic strategies for FD.

CURRENTLY AVAILABLE THERAPY FOR FABRY DISEASE
Enzyme replacement therapy
Currently available Enzyme replacement therapy (ERT) for FD include agalsidase α (Replagal, Takeda),
produced in human fibroblasts and administered at a dose of 0.2 mg/kg biweekly, and agalsidase β
(Fabrazyme, Sanofi Genzyme), produced in Chinese hamster ovary cells and administered at a dose of
1.0 mg/kg biweekly. The mechanism of action underlying ERT involves the intravenous administration of
recombinant α-galactosidase A (α-Gal A), produced through advanced biotechnology, to reduce the
lysosomal accumulation of Gb3 . Agalsidases utilize the mannose-6-phosphate receptor (M6PR), which
[20]
recognizes the enzyme’s mannose 6-phosphate (M6P) residues, to enter lysosomes and perform their
therapeutic function. Recent studies have revealed that additional mechanisms underlie the transport of
ERTs, such as megalin-mediated transport at the renal tubular level, M6PR, megalin, and sortilin-mediated
transport at the podocyte level [21-23] . The efficacy of ERTs and the therapeutic response could, therefore, be
[24]
determined by these mechanisms of drug transport and internalization into cells .

Pegunigalsidase α is a new ERT, produced by Protalix Biotherapeutics in Israel. This drug, recently
approved by the FDA, has improved stability and half-life thanks to PEGylation.

Agalsidase β
Numerous clinical studies have investigated the effects of ERT in FD patients and many studies conducted
[25]
over the years have demonstrated the efficacy of agalsidase β . Agalsidase β has been shown to slow the
progression of renal, cardiac, and cerebrovascular complications in advanced FD patients compared to
placebo, with early treatment initiation being associated with better outcomes .
[26]
Weidemann et al. showed that ERT with agalsidase β improved myocardial function in FD patients by
increasing peak systolic strain rate. These findings suggest that early ERT may mitigate left ventricular
[27]
hypertrophy .
A small observational study confirmed that agalsidase β reduced lyso-Gb3 levels more effectively than
[28]
agalsidase α . Given the strong correlation between plasma lyso-Gb3 levels and disease severity, targeting
this biomarker is crucial for assessing treatment outcomes [29-31] .

Messalli et al. reported significant improvements in cardiac MRI parameters, including reduced myocardial
T2 relaxation time, maximal myocardial thickness, and total left ventricular mass, after 48 months of
[32]
agalsidase β treatment .
Agalsidase β facilitates the clearance of Gb3 deposits, as assessed in renal biopsy studies. The clearance is
time- and dose-dependent, becoming evident after just 5 months of therapy with agalsidase β compared to
placebo, and affects the cells most resistant to treatment, such as podocytes and distal tubular
epithelium [33,34] .