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Table 2 Drug proposed to treat WS

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

Compound Target/mechanism of action Clinical trial status in WS References
4-Phenylbutyric acid (PBA) and tauroursodeoxycholic acid (TUDCA) Chemical chaperones: stabilize protein conformation during folding, ameliorate trafficking of mutant proteins, suppress unfolded protein aggregation   [71]
Dantrolene 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]
Pioglitazone Inhibits inositol triphosphate (IP3R)-mediated release of calcium from the ER   [45, 75,76,77,78]
Rapamycin Reduces cytoplasmic calcium by a mechanism similar to pioglitazone   [76]
Carbachol 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   [71]
Salubrinal 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 [89,90,91,92,93,94]