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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 346

[53]
Hughes et al. conducted a study to assess the long-term efficacy and safety of Migalastat . They studied
patients enrolled in the phase III clinical trial, FACET and ATTRACT, and they found that 97 patients
treated with Migalastat for up to 8.6 years showed a low incidence of FACEs (renal, cardiac and
[53]
neurological events), in both naïve and ERT-experienced patients .

While it remains uncertain whether Migalastat can cross the blood-brain barrier in humans, studies in a
mouse model of FD have shown that Migalastat increases α-Gal A activity and reduces Gb3 levels in most
tissues, including the brain [54,55] .

NEW EMERGING THERAPIES
New potential therapeutic drugs are being explored in studies, including second-generation enzymes,
substrate reduction therapies, and gene- and mRNA-based therapeutic strategies [Table 1].

Enzyme replacement therapy
Moss α-galactosidase
Moss-α-galactosidase (moss-αGAL) is a plant-derived variant of α-galactosidase engineered to possess a
N-glycosylation profile dominated by mannose-terminated glycans. Developed as an enzyme replacement
therapy for FD, its non-phosphorylated form has demonstrated efficacy in both in vitro and murine models.
While its cellular localization in heart and kidney tissues is comparable to that of agalsidase α, moss-αGAL
exhibits a stronger affinity for kidney tissue .
[56]
A phase 1 clinical trial confirmed the safety and tolerability of a single dose of moss-αGAL, accompanied by
a sustained reduction in Gb3 excretion. Leveraging the mannose receptor, which is expressed on
macrophages, endothelial cells, and kidney cells, moss-αGAL shows promise for further development. The
positive results from phase 1 trials have paved the way for ongoing phase 2/3 clinical trials .
[57]

Substrate reduction therapies
The substrate reduction therapy (SRT) aims to decrease the deposits due to the accumulation of metabolites
caused by the enzymatic defect, by blocking glucosylceramide synthase (GCS), thereby decreasing the
synthesis of precursors to Gb3. The primary advantages of SRT are its oral administration and its ability to
cross the blood-brain barrier. In patients with residual galactosidase-α activity (non-classical mutations),
SRT may effectively reduce substrate levels to a point where the remaining enzyme can manage the
metabolic load. Alternatively, SRT can be combined with ERT if α-GalA activity is below 1% [11,58] .

Indeed, data from Fabry mice studies showed that adding substrate reduction to ERT may offer both
[59]
complementary and synergistic benefits in the management of FD .
It is essential to operate with precaution in dosing, because complete inhibition of a single enzyme can
disrupt cellular homeostasis, influencing processes such as apoptosis, cell growth, and differentiation.

Two molecules were developed for Fabry disease: Venglustat, produced by Sanofi Genzyme and Lucerastat,
produced by Idorsia Pharmaceuticals, both of which inhibit glucosylceramide synthase (GCS).

Venglustat
Venglustat is a ceramide-based small molecule designed to inhibit GCS. By blocking GCS, Venglustat
reduces the production of glucosylceramide, a precursor to glycosphingolipids.