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Page 6 of 11 Feriozzi et al. Rare Dis Orphan Drugs J 2024;3:11 https://dx.doi.org/10.20517/rdodj.2023.37

THE ROLE OF THERAPY IN MODULATING THE PATHOGENIC MECHANISMS
ERT with two molecules [agalsidase alpha and beta] has been available for Fabry disease for twenty years.
Recently, oral treatment with a chaperone [migalastat] of alpha-galactosidase A has also been prescribed for
patients carrying amenable mutations. Migalastat can link and stabilize the mutated enzyme and increase
the lysosomal trafficking and enzyme activity. These therapies have undoubtedly changed the outcomes of
Fabry patients, stopping or slowing down the progression of the disease. Notably, the scientific community
agrees with two opinions: the best results were obtained in patients who start therapy early, and late
treatment prescription does not have the same efficacy as early [2,47] .

Gene therapy for Fabry disease is still being carried out in a few world centers and represents an innovative
solution. In Canada, five patients were treated with lentivirus-mediated gene therapy. After 3-5 years, there
is persistent polyclonal engraftment with plasma and leukocyte GLA activity above baseline, with a fall in
[48]
Gb3 and lysoGb3 levels . However, these procedures are expensive and not consistently successful, and
some trials have been stopped.

SGLT2 inhibitors (SGLT2i), drugs blocking tubular glucose reabsorption, have demonstrated their efficacy
in reducing the progression of renal damage in nephropathies and cardiovascular mortality. SGLT2i work
indirectly by interfering with the glomerular-tubular balance and increasing tubular urinary flux. Most
relevant studies were conducted on diabetic nephropathy in chronic renal disease, IgA nephropathy, and
focal segmental glomerulosclerosis (FSGS). Recently, SGLT2i was proposed as a therapy for Fabry
[49]
nephropathy, and a study is ongoing .

During the last few years, several pieces of evidence have been described that can substantially explain the
different results according to the therapy timing. Braun et al. studied human podocyte cultures with
reduced alpha-galactosidase A activity . These podocytes presented Gb3 deposition, displayed dysfunction
[50]
of autophagic mechanisms, and released a panel of profibrotic cytokines. Upon addition of recombinant
alpha-galactosidase A, these podocytes showed complete clearance of Gb3; however, glycolipid clearance
was not associated with the correction of the altered cytokine signaling pathways. The authors suggest that a
point of no return can exist, after which the alpha-galactosidase A cannot wholly correct cellular
dysfunction despite eliminating Gb3.

Jehn et al. studied the altered cellular pathways in podocytes, endothelial cells, and urinary-derived cells
from patients . With proteomic analysis, GLA-deficient cells displayed dysregulated protein levels
[51]
involved in lysosomal traffic, cell-cell interactions, and other activities. The rescue with inducible GLA
partially restored the protein expression through a sophisticated technique with lentivirus [CRISPR/Cas9
mediated GLA]. These results proved that a deficiency of GLA activity determines severe changes in
physiological pathways in all kinds of cells, and the therapy cannot completely restore physiological
functions.

Recently, Braun et al. published a paper confirming that the therapy alleviates lysosomal dysfunction but
cannot always reverse organ damage . ERT reduced Gb3 accumulation in podocytes in renal biopsies from
[52]
Fabry patients, but notably, the foot-processes effacement persisted in some tracts. A CRISPR/CAS9-
mediated alpha-galactosidase knockout podocyte cell line confirmed the ability of ERT to clear cellular Gb3
deposition but without resolving lysosomal dysfunction. Finally, a transcriptomic investigation identified a
protein alpha-synuclein [SNCA] as a mediator of lysosomal dysfunction. Alpha-synuclein is a protein that
regulates synaptic vesicle trafficking and subsequent neurotransmitter release. It has been implicated in
other lysosomal diseases and is well-known for its role in Parkinson's disease. Synuclein is negatively