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Page 6 of 11 Schiffmann. Rare Dis Orphan Drugs J 2024;3:4 https://dx.doi.org/10.20517/rdodj.2023.50

Two additional therapeutic modalities are being tested for Fabry disease. The first is substrate synthesis
reduction or SRT. Its goal is to decrease the synthesis of glycosphingolipids at the step of glucosylceramide
[64]
by inhibiting its synthetic enzyme UDP-glucose: N-acylsphingosine glucosyltransferase . Two compounds
have been tried in Fabry disease - venglustat and Lucerastat [64,65] . In clinical trials of both drugs, virtually all
participants had the classic form of Fabry disease (no residual α-galactosidase A activity); a
pharmacodynamic effect was observed with a reduction in circulating globotriaosylceramide and lysosomal
inclusions in skin biopsies, but no clinical benefit was found [64,66] . The negative clinical findings can be
explained mainly by the absence of residual enzyme activity in adult study participants. The presence of
sufficient residual α-galactosidase A activity may be central for the restoration of metabolic homeostasis that
allows the clearance of excess substrate by the deficient enzyme activity. That residual enzyme activity is
central to the efficacy of SRT in Gaucher disease, in which all patients have some residual enzyme (acid
beta-glucosidase) activity . Therefore, since all patients with later onset Fabry disease have residual α-
[67]
galactosidase A activity, clinical trials with SRT should focus on this group of patients, with a particular
emphasis on their heart disease - the most significant unmet need in Fabry disease . The second possible
[1]
reason for the lack of efficacy of SRT in Fabry disease is the likely existence of α-galactosidase A substrates
that are not glycosphingolipids. Evidence for that was found in the study of the dorsal root ganglia in the
[69]
[68]
Fabry knockout mouse model . This mouse displays well the small-fiber neuropathy of Fabry disease .
Plant lectin isolectin B4 (IB4)-positive neurons in the dorsal root ganglion express surface carbohydrates α-
D-galactose groups conjugates, have small size cell bodies, and primarily give rise to unmyelinated fibers
and small myelinated fibers, many of which are nociceptive and thought to be involved in a small-fiber
neuropathy such as the one affecting patients with Fabry disease [68,70] . IB4 positive neurons stain was
stronger in the Fabry mouse compared to wild type, but almost all these cells were negative for
globotriaosylceramide, suggesting that these cells have a different α-D-galactose substrate .
[68]

Gene therapy for Fabry disease is also being developed. The main effort currently involves the use of adeno-
associated virus (AAV)-based gene supplementation . The approach that seems most frequently taken is to
[71]
use the natural affinity of AAV to hepatic cells to transduce hepatocytes with the GLA cDNA [72,73] .
Transduced liver cells produce large amounts of α-galactosidase A that is then excreted into the circulation
to be taken up by cells and organs, akin to a continuous form of ERT. Using this liver-targeting approach,
STAAR, a Phase 1/2 study of Isaralgagene civaparvovec (ST 920) gene therapy is the program furthest in its
development. ST-920 is based on the hybrid AAV vector AAV2/6, in which hybrid AAV vectors have been
engineered using the capsid protein of AAV6 serotype and the genome of AAV serotype 2 [74,75] . This
program has had no safety concerns, and patients do not routinely take immune modulators such as
corticosteroids. Circulating α-galactosidase A activity has been relatively stable for up to two years, but
plasma lyso-Gb3 tended to increase upon stopping ERT . Reduction of lysosomal inclusions in peritubular
[75]
endothelial cells was seen in one of two patients tested, and reduced podocyturia was found in two
[75]
13
patients . The maximal dose of 5X10 vector genomes/kg was tested in this trial phase, and it is this dose
that was chosen for further clinical evaluation, including a phase 3 trial . Other biotechnology companies
[75]
such as UniQure and Spark Therapeutics have expressed their intention to use a similar gene therapy
approach to treat Fabry disease. Another interesting application of AAV gene transfer is to deliver the GLA-
[76]
cDNA via recombinant AAV6 (rAAV6) transduction to peripheral blood human B cells ex vivo . Here the
AAV delivers the gene to a safe harbor locus in the patient’s B cells using a CRISPR system by the process of
nucleofection. The ex vivo gene-engineered and expanded B cells are then re-infused into patients in the
hope of providing a consistent source of the deficient enzyme .
[76]

Since ERT has not adequately addressed the cardiovascular manifestations of Fabry disease and circulating α
-galactosidase A is not taken up efficiently by cardiomyocytes, direct transduction of the affected organs,