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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 348

Lucerastat
Lucerastat, or N-butyldeoxygalactonojirimycin, is a soluble, low-molecular-weight molecule derived from
galactose. It is administered orally and functions as a GCS inhibitor, restoring the normal balance of
[64]
glycosphingolipid (GSL) synthesis, breakdown, and cellular transport .

Two separate randomized, double-blind, placebo-controlled studies evaluated the safety, tolerability, and
pharmacokinetics of oral Lucerastat in healthy male volunteers.

In the single-ascending dose trial (SAD), 31 males got placebo or Lucerastat (a single oral dose of 100, 300,
500, or 1,000 mg). Other 8 subjects took 1,000 mg Lucerastat or placebo bis in die (two doses separated by
12 h).

In the multiple-ascending dose trial (MAD), 37 volunteers received either placebo or 200, 500, or 1,000 mg
Lucerastat, twice daily for 7 consecutive days. To assess the impact of food on drug absorption, 6
participants in the 500 mg dose group received Lucerastat with or without food.

Data from both the SAD and MAD studies indicated that Lucerastat was well tolerated overall. These
promising results have led to further investigations of SRT with Lucerastat in FD patients .
[64]

In a single-center, open-label, randomized study, patients were randomized to receive Lucerastat in addition
to standard care, including ERT (10 patients), or ERT alone (4 patients). The Lucerastat treatment group
showed a significant reduction in plasma concentrations of Gb3 and its precursors, glucosylceramide and
lactosylceramide. However, no clinical improvement in cardiac and renal functions was observed, likely due
to the study’s short duration of only 12 weeks .
[65]
Additional studies are ongoing to further evaluate the efficacy and safety of Lucerastat in adult FD
patients .
[66]

Gene and mRNA-based therapies
The primary goal of gene therapies is a long-term treatment strategy that addresses all damaged cells and
tissues in patients with FD.

In recent years, numerous preclinical studies have been conducted both in vivo and ex vivo, utilizing a
variety of viral vectors, such as retroviral, lentiviral, adenoviral, and non-viral vectors.

The single-arm study NCT02800070 enrolled five male patients with classic FD who received autologous
CD34+ hematopoietic stem cells engineered to express α-galactosidase A using a lentiviral vector. Initial
data assessed the safety and tolerability, showing a reduction in plasma and urine levels of Gb3 and
lyso-Gb3. Moreover, bone marrow cells, plasma, and leukocytes exhibited normal range of α-gal A activity,
while the vector was detected in the blood. Three of the five patients chose to stop the enzyme therapy even
if the study is ongoing .
[67]
Studies using Fabry knockout mice have employed recombinant adenoviral vectors expressing human
α-galactosidase A (Ad2/CEHalpha-Gal and Ad2/CMVHIalpha-Gal). These studies demonstrated a
restoration of α-galactosidase A levels to within the normal range across multiple tissues, including liver,
lung, kidney, heart, spleen, and muscle. Additionally, a significant decrease in Gb3 levels was observed in all
tissues, with levels approaching normal values within 6 months of treatment. On the other hand, a rapid