Developments in the treatment of Fabry disease

Abstract

Enzyme replacement therapy (ERT) with recombinant α‐galactosidase A (r‐αGAL A) for the treatment of Fabry disease has been available for over 15 years. Long‐term treatment may slow down disease progression, but cardiac, renal, and cerebral complications still develop in most patients. In addition, lifelong intravenous treatment is burdensome. Therefore, several new treatment approaches have been explored over the past decade. Chaperone therapy (Migalastat; 1‐deoxygalactonojirimycin) is the only other currently approved therapy for Fabry disease. This oral small molecule aims to improve enzyme activity of mutated α‐galactosidase A and can only be used in patients with specific mutations. Treatments currently under evaluation in (pre)clinical trials are second generation enzyme replacement therapies (Pegunigalsidase‐alfa, Moss‐aGal), substrate reduction therapies (Venglustat and Lucerastat), mRNA‐ and gene‐based therapy. This review summarises the knowledge on currently available and potential future options for the treatment of Fabry disease.

Fabry Disease Therapy: State-of-the-Art and Current Challenges

“…However, concerns about immunogenicity have also been raised, because of the different glycosylation pattern of a plant-derived protein and the PEG component. Of note, the extended half-life may also interfere with the laboratory assays for anti-drug antibodies detection, as the circulating enzyme at the sampling time may bind antibodies and prevent their detection [13]. Table 3.…”

“…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]…”

“…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] Moss-derived α-galactosidase A is produced in the moss Phycomitrella patens and is a glycoengineered variant devoid of α-1,3-fucose and β-1,2-xylose residues on its N-glycans that are plant-specific and may elicit immunogenic response in mammals [104]. Being plantderived, this enzyme does not display M6P on their surface glycans; instead, it carries >90% mannose-terminated glycans [104].…”