Table 3.

Potential advantages and limitations of emerging therapies of FD.

	Potential Advantages	Potential Limitations
Pegunigalsidase alfa	▪Higher plasma half-life [100,101,102], allowing a monthly infusion [102]	▪Anti-drug antibodies in 19% of cases [101] ▪Plant-derived protein with a different glycosylation pattern—possible immunogenicity issues? [100] ▪Unclear effect on the immune system [13] ▪No crossing of the blood–brain barrier [13] ▪Lifelong therapy requiring intravenous administration [13]
Moss-derived α-galactosidase A	▪Higher cellular uptake via the mannose receptors [104,105]	▪Plant-derived protein with a different glycosylation pattern—possible immunogenicity issues? [104] ▪Unclear effect on the immune system [104] ▪No crossing of the blood–brain barrier [13] ▪Lifelong therapy requiring intravenous administration [13]
Substrate reduction therapy	▪Oral administration [13] ▪Non-immunogenic [13] ▪Possible crossing of the blood-brain barrier [106]	▪Complete block of a single enzymatic reaction could potentially disrupt the cell homeostasis [13] ▪May not be sufficient as monotherapy for patients with minimal/no residual enzymatic activity [13]
mRNA therapy	▪Potential for a larger interval between infusions [107,108] ▪Uses endogenous protein translation system to ensure proper folding, glycosylation, and intracellular trafficking of α-galactosidase A [13] ▪No risk of insertional mutagenesis [13]	▪Primarily targets hepatocytes [13] ▪Unclear effect on immune system in classic males [13]
Gene therapy	▪Introduces a correct version of the GLA gene [12] ▪Uses endogenous protein translation system to ensure proper folding, glycosylation, and intracellular trafficking of α-galactosidase A [13]	▪Targeting all affected cell types and tissues is a challenge [13] ▪Risk of insertional mutagenesis [13] ▪Unclear effect on immune system in classic males [13]