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Table 2 Drug proposed to treat WS

From: Wolfram syndrome, a rare neurodegenerative disease: from pathogenesis to future treatment perspectives


Target/mechanism of action

Clinical trial status in WS


4-Phenylbutyric acid (PBA) and tauroursodeoxycholic acid (TUDCA)

Chemical chaperones: stabilize protein conformation during folding, ameliorate trafficking of mutant proteins, suppress unfolded protein aggregation




Blocks ryanodine receptor in the ER membrane: stabilize ER calcium level by suppressing the efflux of calcium from ER to cytosol

Clinical trial of dantrolene sodium in pediatric and adult patients with WS, NCT02829268

[28, 72, 74]


Inhibits inositol triphosphate (IP3R)-mediated release of calcium from the ER


[45, 75,76,77,78]


Reduces cytoplasmic calcium by a mechanism similar to pioglitazone




Muscarinic receptor 3 (M3) agonist: mobilizes intracellular calcium stores and potentiates glucose-stimulated insulin secretion


[79, 80]

Liraglutide, exenatide, semaglutide

Glucagon-like peptide-1 receptor (GLP-1R) agonists. They activate PERK-ATF4 pathway and interfere with the ER unfolded protein response


[28, 81,82,83,84,85,86]

Sitagliptin, vildagliptin, gemigliptin

Inhibitors of dipeptidyl peptidase-4 (DPP-4), an enzyme that deactivates GLP-1, thus also increasing GLP-1 levels




Selective inhibitor of the eIF2α phosphatase


[87, 88]

Valproate acid (VPA)

Promotes the expression of both WFS1 and ER chaperones and attenuates ER-induced apoptosis

Efficacy and safety trial of sodium valproate in pediatric and adult patients with WS, NCT03717909