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Schiffmann. Rare Dis Orphan Drugs J 2024;3:4 https://dx.doi.org/10.20517/rdodj.2023.50 Page 7 of 11

and especially the heart, is an important approach to investigate. A program has been developed (4D-310)
that uses a synthetic cardiotropic AAV vector invented through directed evolution to deliver a human GLA
[77]
transgene to cardiomyocytes and other affected organs following intravenous administration . The
transgene expression is driven by a ubiquitous promoter. Preliminary results of cardiac activity at 12
months post-4D-310 administration showed improvement in left ventricular contractility, exercise capacity,
[77]
and quality of life in the first four patients in this study . Confirmed transgene delivery and expression in
cardiomyocytes was found on cardiac biopsy in one patient . Because of the propensity of the 4D-310
[77]
capsid to activate complement with sometimes secondary atypical hemolytic uremic syndrome in some
patients, this study is at the time of this writing in FDA clinical hold. The company (4D Molecular
Therapeutics) has agreed with the FDA on a plan that will allow the resumption of enrollment.

An approach using lentiviral-mediated gene transfer into hematopoietic stem cells was tested for several
years with some pharmacodynamic success, but this program was eventually discontinued .
[78]

SUMMARY AND CONCLUSIONS
α-Galactosidase A residual activity is the central prognostic indicator of disease severity. As a result, every
GLA variant, particularly a missense mutation, is typically categorized as associated with classic or late-onset
disease. Some GLA variants are benign because they lead to a residual enzyme activity that is above the
disease threshold. We and others recently found that some missense variants, such as A143T, are often
benign but, in other cases, are associated with low α-galactosidase A activity, leading in many cases to the
phenotype of late-onset Fabry disease. This finding has epidemiologic implications since the A143T variant
is quite common, and when included in the calculation of disease incidence, it results in a significantly
higher prevalence of Fabry disease than previously thought [14,79] .The mechanism of Fabry disease is still
incompletely understood, but one must appreciate that some abnormalities may be adaptive in nature and
therefore should not be selectively reversed.

We can help patients with Fabry disease by using non-Fabry-specific therapy and Fabry-specific therapy
such as ERT. The latter has shown some efficacy, but in most patients on ERT, the disease continues to
progress. Pharmacological chaperone migalastat has significant theoretical advantages. Migalastat
completely corrects the metabolic abnormality in patients with the most common amenable missense
mutations and should certainly be the preferred Fabry-specific therapy in such patients. SRT and gene
therapy are being developed for Fabry disease, but both approaches have pitfalls that must be overcome.

DECLARATIONS
Acknowledgments
The manuscript was edited and proofed by Marie-Anne Schiffmann.

Authors’ contributions
The author contributed solely to the article.

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.