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Page 307 Zhang et al. J Transl Genet Genom 2024;8:302-11 https://dx.doi.org/10.20517/jtgg.2024.39

Gene therapy operates on the principle of introducing DNA that encodes the α-Gal A protein into the
patient’s cells. Introducing a therapeutic gene, along with subsequent endogenous cellular expression, will
facilitate the production of the enzyme that was originally scarce, potentially altering the course of FD
[36]
fundamentally . Currently, phase 1/2 clinical trials are exploring the use of in-vivo gene therapy with
various biological agents, including adeno-associated virus vectors and non-viral vectors.

Research has shown that although ERT can reduce Gb3 accumulation in podocytes, its effect on podocyte
damage repair is not obvious . In addition, the CRISPR/Cas9-mediated knockout of alpha galactose
[23]
glucoside enzyme of Sertoli cell model confirmed that although ERT can reverse the accumulation of Gb3, it
does not solve the problem of lysosome dysfunction . Further transcriptome and quantitative proteomic
[37]
analysis found that SNCA accumulation is the key factor in podocyte damage . Genetic and
[23]
pharmacological inhibition of SNCA can improve the structure and function of lysosomal podocytes in
Fabry disease, demonstrating an effect that surpasses that of ERT [23,38] .

In addition, it has been suggested that podocyte injury in Fabry disease is related to the dysregulation of the
autophagy pathway. In podocytes, upregulation of the autophagy marker microtubule-associated protein 1
light chain 3 (LC3-II) was observed, which may be related to defects in mTOR and AKT signaling
pathways . mTOR is a key negative regulator of autophagy formation, and AKT is its upstream regulator,
[39]
both of which show reduced activity in Fabry disease . Reduced mTOR phosphorylation results in a rise in
[39]
autophagosomes. However, the continuous overactivation of autophagy can cause podocyte injury. Li et al.
proposed that a negative feedback loop might exist, where the surge in autophagosomes could reactivate
mTOR . This reactivation would suppress further autophagosome creation and promote lysosomal
[40]
regeneration, possibly serving as a cellular defense against autophagy-induced cell death . Accumulation of
[40]
Gb3 impairing mitochondrial function can disrupt mTA1 activity, causing spontaneous effects and energy
deficits. Therefore, mTOR-dependent pathways are pivotal in regulating autophagic-lysosomal fusion and
mitochondrial function. Disruption of the lysosome-autophagy-mitochondria axis is a significant factor in
the organ damage associated with FD . Additionally, this interaction may also offer a new direction for
[41]
[39]
treating podocyte damage in Fabry disease .
Supportive therapy
Controlling proteinuria is crucial for maintaining renal function in FD patients. Medications such as
angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) have been
shown to slow the progression of renal disease in FD by reducing damage to podocytes [42,43] . Warnock et al.
demonstrated individuals who sustained a UP/Cr ratio < 0.5 g/g or a 50% reduction from their initial UP/Cr
ratio through the use of an ACEi or ARBs experienced a less decline in eGFR (-3.6 mL/min), in contrast to
those who failed to reach these criteria (-7.0 mL/min) .
[43]

Initially developed to reduce blood glucose levels, SGLT2 inhibitors have become increasingly recognized
for their role in CKD management. Recently, SGLT2 inhibitors have gained approval for treating CKD
progression in patients with proteinuria. Battaglia et al. suggested that SGLT2 inhibitors can mitigate
damage to podocytes by targeting the pathogenetic mechanisms like oxidative stress and inflammation that
[44]
ERT or chaperone therapy alone might not fully resolve . This study is the first to assess the effect of
Dapaglifozin in FD patients with albuminuria and renal function progression.

PODOCYTE REGENERATION
Professor Romagnani from Italy, as early as 2013 after a series of research results, accurate account of the
inherent in the human renal unit cells, especially the glomerular cells and renal tubular epithelial cells of