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Page 26 of 34 West et al. Rare Dis Orphan Drugs J 2024;3:22 https://dx.doi.org/10.20517/rdodj.2023.61

CRISPR/Cas techniques have been successfully applied to both create and treat animal models of Fabry
[190]
diseases . With this technique, DNA variants can be corrected in vivo. There remain concerns about the
safety of these techniques in humans as well as the number of cells needed to be corrected to effect clinical
benefits. Some investigations in animal models suggest that achieving 10% of normal α-Gal activity may be
sufficient , but the optimal target α-Gal activity in human studies remains undefined.
[191]

QUESTIONS ABOUT FABRY NEPHROPATHY STILL TO BE ANSWERED
Important questions remain to be answered about Fabry kidney disease. These are some for future research.

1. Define the natural history of Fabry disease including nephropathy; why is the prevalence of kidney
disease in heterozygotes less than that of cardiac disease or stroke?

2. Determine how to predict which heterozygotes will go on to develop progressive kidney disease so that
treatment can be started early;

3. Determine which ERT is best for different patient groups - males, females, classic vs. late-onset disease; is
dose important in adults?

4. Determine if combination therapy is superior to monotherapy, i.e., ERT + chaperone; are these
treatments of additional benefits?

5. Determine the optimal age to start therapy, recognizing that this will vary among different patient groups;

6. Determine how to best deal with patients who have high levels of neutralizing anti-drug antibodies that
are limiting treatment response;

7. Determine what the target α-Gal activity should be with gene and cell therapies;

8. Determine if plasma lyso-Gb3 or another biomarker can serve as a surrogate marker for clinical trials in
Fabry nephropathy.

SUMMARY
Fabry nephropathy is a rare cause of CKD due to the deficiency of the lysosomal enzyme α-Gal. Its
importance lies in the fact that it is a treatable cause of CKD. It is an X-linked disorder, with heterozygous
females being less affected than males. It is difficult to recognize due to its rarity but also its shared clinical
features with more common conditions. Clinical features are highly variable, with an early-onset classic
severe phenotype and a later-onset phenotype. Family screening and high-risk screening of patients with
CKD or on dialysis is best done with a combination of lyso-Gb3, α-Gal activity, and GLA analysis, as many
females have normal α-Gal activity. Pathogenesis relates to the deposition of the enzyme substrate Gb3 and
its metabolite lyso-Gb3, which together cause widespread abnormalities in cell signaling and homeostasis.
In the kidney, the podocyte is the main target due to its inability to replicate and large accumulation of Gb3
over time. Podocyte damage from Gb3 results in podocyturia with focal glomerulosclerosis and increasing
proteinuria. Control of proteinuria as the major factor promoting loss of GFR is one of the cornerstones of
management. Treatment with recombinant ERT or pharmacologic chaperone is available. The best results
come with early diagnosis and initiation of treatment, although the optimal age for start is still uncertain.
Treatment will slow or stabilize the eGFR slope but does not lower proteinuria. ERT effect may be limited