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Page 345 Giliberti et al. J Transl Genet Genom 2024;8:340-54 https://dx.doi.org/10.20517/jtgg.2024.41

[47]
promising new therapeutic alternative for FD .

Chaperone therapy
Migalastat
Although ERTs are effective, they have several limitations: the need for intravenous administration, which
may reduce patient compliance or negatively impact the quality of life; the inability to cross the blood-brain
barrier; and the potential development of anti-drug antibodies.

An alternative treatment for FD is chaperone therapy, which aims to assist mutated α-GAL A proteins in
correctly folding, thereby enhancing their stability and function within the lysosome. However, it is only
effective for patients with specific “amenable” mutations in the GLA gene genetic variants that result in a
qualitatively anomalous production of the misfolded, unstable enzymes. Amenable mutations can be
responsible for both classic and late-onset phenotypes .
[48]

Migalastat, a representative chaperone drug, binds to a specific sugar molecule (iminosugar) within the
catalytic domain of the mutant α-GAL A. This binding helps the enzyme fold correctly and facilitates its
transport to the lysosome, where it can degrade the accumulated substrate (Gb3).

A mutation is considered responsive to migalastat if α-Gal A activity increases by at least 1.20 times the
baseline level, with an absolute increase of at least 3.0% in wild-type α-Gal A activity when exposed to
10 μmol/L migalastat .
[48]

Migalastat is a potent inhibitor of α-GAL A at high doses. However, at lower doses, it paradoxically
increases enzyme activity for specific GLA variants . This seemingly contradictory effect is believed to
[49]
occur because iminosugar initially binds to the enzyme, promoting proper folding. Once the enzyme
reaches the lysosome, the competitive inhibitor (iminosugar) is displaced by the natural substrate, allowing
α-GAL A to function normally. Migalastat is an oral medication administered at a dose of 123 mg every
other day. It was approved by the European Medicines Agency (EMA) in 2016 for the treatment of FD
2
patients aged 16 years and above, with an eGFR ≥ 30 mL/min/1.73 m and mutations amenable to
chaperone therapy .
[50]
The FACETS trial compared chaperone therapy (Migalastat) with placebo in ERT-naïve patients with
Migalastat-responsive GLA mutations. After 6 months of treatment, Migalastat significantly reduced plasma
lyso-Gb3 levels and the number of Gb3 inclusions in kidney interstitial capillaries compared to placebo.
Additionally, the first 6 months of Migalastat treatment resulted in a decrease in the total Gb3 inclusion
volume per podocyte in kidney biopsies, which correlated with a reduction in the mean podocyte
[51]
volume . Furthermore, a significant reduction in the mean LVMI was observed at the 24-month mark
compared to baseline .
[5]

The ATTRACT trial evaluated the effectiveness of Migalastat in ERT-experienced patients with amenable
GLA mutations. Patients were randomized to either switch to Migalastat or continue ERT. After 18 months,
Migalastat significantly reduced the mean left ventricular mass index compared to the ERT group, which
showed no significant change. However, the design of this study has some limitations. The initial cohort
included patients with non-amenable mutations in the Migalastat arm and a higher discontinuation rate in
the ERT arm. As a result, only a small number of ERT patients (16 patients) remained evaluable by the
[52]
study’s conclusion, which may potentially influence the reliability of the results .