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Page 349 Giliberti et al. J Transl Genet Genom 2024;8:340-54 https://dx.doi.org/10.20517/jtgg.2024.41

[68]
decline in enzyme expression was observed by 12 weeks .

Other phase 1/2 studies testing in vivo gene therapy are currently underway. Various biological agents
utilizing adeno-associated virus vectors are under investigation, including the liver- and cardiac-targeted
[71]
[70]
4D-310 , as well as the liver-targeted ST-920 and FLT190 .
[69]
Preliminary data from these studies show an increase in α-Gal A activity and a reduction in Gb3 levels.

mRNA-based therapy is one of the promising future therapeutic strategies for FD, as it enables endogenous
α-Gal A expression in the targeted tissues, offering long-term safety and no immunogenicity. Unlike DNA-
based therapies, mRNA-based therapy does not carry the risk of insertional mutagenesis.

However, the effects of mRNA-based therapy are transient, thus requiring repeated administration.

A preclinical study evaluated the systemic delivery of mRNA encoding human α-Gal A in wild-type (WT)
mice, α-Gal A-deficient mice, and WT non-human primates (NHPs). Data indicate a dose-dependent
increase in protein activity and subsequent substrate reduction in GLA-deficient mice following a single
administration of h-α-Gal A mRNA. Importantly, these effects were sustained, with prolonged half-lives and
substrate reduction observed in tissues and plasma for up to 6 weeks. Repeated administrations of h-α-Gal
[17]
A mRNA demonstrated continued efficacy, safety, and pharmacological activity in a Fabry mouse model .

SYMPTOMATIC TREATMENT
The specific therapy for FD should be integrated with adjunctive interventions to manage the cardiac, renal,
neurological, and other complications arising from chronic tissue damage .
[72]

For renal management, sodium-glucose cotransporter-2 inhibitor (SGLT2i), ACE inhibitors (ACEI), or
angiotensin receptor blockers (ARB) are recommended to control albuminuria and slow the progression of
chronic kidney disease (CKD). Standard CKD management guidelines should be followed for the use of
[73]
statins and the prevention of CKD-related mineral bone disorders (CKD-MBD) . For patients progressing
to renal failure, dialysis or kidney transplantation is required. Furthermore, living-related donors must be
tested to ensure they are negative for FD.

Cardiac complications are typically managed by ACEI or ARB, while beta-blockers should be used
cautiously. Amiodarone should be avoided, especially in the case of ERT, because of its possible suppressive
impact on α-galactosidase (α-GAL) enzyme activity. For symptomatic bradycardia or significant AV
conduction abnormalities, permanent pacemaker insertion may be indicated . Patients with atrial
[74]
fibrillation should receive lifelong anticoagulation, and in cases of malignant arrhythmias, implantable
[75]
cardioverter-defibrillators (ICD) should be considered .

Cerebrovascular complications require stroke prophylaxis with antithrombotic agents (e.g., aspirin or
clopidogrel) for secondary prevention. In patients with atrial fibrillation, anticoagulation with warfarin or
newer agents is recommended .
[76]

Neuropathic pain is managed using anticonvulsants such as gabapentin or pregabalin as first-line agents,
with opioid agonists considered for severe pain crises. Lifestyle modifications, including avoiding
temperature extremes and maintaining proper hydration, are important to prevent pain exacerbations .
[77]