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West et al. Rare Dis Orphan Drugs J 2024;3:22 https://dx.doi.org/10.20517/rdodj.2023.61 Page 25 of 34

advantage over pre-existing forms of ERT is unknown. ADA have been described to this ERT with transient
altered pharmacokinetics with lower Cmax and T blood levels that returned to normal as the antibodies
½
[166]
spontaneously disappeared . In a study of 22 patients on agalsidase-alfa switched to pegunigalsidase,
2
eGFR slope went from -5.90 to -1.19 mL/min/1.73 m /yr and mean plasma lyso-Gb3 fell by 31% . This
[167]
improvement was possibly due to the dose differences (0.2 vs. 1.0 mg/kg) between these ERTs, as another
study of 77 patients comparing agalsidase-beta at 1.0 mg/kg dose with pegunigalsidase did not find any
difference in eGFR slopes or plasma lyso-Gb3 between these ERTs . A potential advantage of
[168]
pegunigalsidase is that there may be less cross-reactivity with ADA to the other forms of ERT. Lenders et al.
(2022) has reported that ADA to agalsidase versions of ERT have decreased affinity for the pegunigalsidase
[180]
molecule; other data suggested possible masking of some epitopes by the PEG moieties .

Substrate reduction therapy
Substrate reduction therapy (SRT) involves the inhibition of the enzyme glucosylceramide synthase
upstream in the glycosphingolipid metabolic pathway. This results in a reduction in Gb3 levels in plasma
and urine independent of α-Gal A activity. Several of these oral iminosugars are in phase III trials
(ClinicalTrials.gov NCT03425539 Lucerastat, Idorsia Pharmaceuticals Ltd; NCT06114329 AL01211,
AceLink Therapeutics Inc; NCT05206773 Venglustat Sanofi-Aventis LLC) [181,182] . These drugs have the
advantage that they are taken orally and should not be influenced by ADA. While SRTs might also work
synergistically with ERT or chaperone to lower substrate and metabolite levels even more, current research
focuses solely on their efficacy as single agents. Using two drugs to treat Fabry disease could well double the
cost, which might outstrip any combined benefit.

Gene and cell therapies
The goal in gene therapy is to bring about continuous α-Gal production from a transduced cell population
(hematopoietic stem cells, cardiomyocytes, hepatocytes) to enable α-Gal delivery to non-transduced cells in
target organs such as the kidney and heart at levels sufficient to reverse the metabolic defect of Fabry
disease. This is also dependent on the ability of the target cells to take up α-Gal from the circulation via
various transmembrane transport systems. Pre-existing antibodies to ERT and to the adeno-associated virus
(AAV) vector may complicate these studies. To date, however, none of the human studies have provided
direct evidence of delivery of over-expressed or engineered a-gal into the kidney or heart tissues. Gene
therapy by ex vivo lentivirus-mediated autologous hematopoietic stem cells or in vivo AAV delivery has
been tried with some early positive results [183,184] . Duration of the effect from gene therapy is unknown, but
the FACTS study using ex vivo lentivirus-mediated autologous hematopoietic stem cells has shown
sustained effects at the 5-year follow-up (unpublished data. M. West). A number of pharmaceutical
companies have quickly joined and then withdrawn from this field in the last 4 years, perhaps reflecting the
challenges of gene therapy in both Fabry disease and other metabolic diseases, including significant
complications such as atypical hemolytic uremic syndrome and death [185,186] . As gene therapies are also being
developed for other lysosomal diseases, continued progress is expected in this field.

Recent T cell- and B cell-mediated techniques for delivery of enzyme therapy have been proposed, which
may be simpler and less expensive than gene therapy but await human trials [187,188] . As these techniques do
not involve immunosuppression or in vivo cell transduction, fewer adverse effects and hospital days would
be required with reduced cost, but the duration of effect might be less than with gene therapy.

Nucleoside-modified messenger RNA was used successfully to restore α-Gal activity with Gb3 reduction
and restoration of lysosomal protein levels in a model of cardiac Fabry disease, using induced pluripotent
[189]
stem cells-derived human cardiomyocytes .