Table 1:

List of candidate treatments for Wolfram syndrome (WS). In black are drugs that have been tested in in vivo or in vitro models of WS. In blue are proposed drugs and hypothesized mechanisms that should be assessed in future studies. FDA: U.S. Food and Drug Administration; NCT: Clinicaltrials.gov identifier; ER: endoplasmic reticulum; Ca²⁺: calcium; T2: type2; SERCA: sarcoendoplasmic reticulum Ca2+ transport ATPase; GLP1R: glucagon-like peptide-1 receptor; MANF: mesencephalic astrocyte-derived neurotrophic factor; Akt: protein kinase B.

Drugs	Approved in humans? (FDA?; indication)	Clinical trial for WS	Proposed mechanism of action in WS
Targeting disrupted Ca2+ signaling (drug repurposing)
Dantrolene [31]	yes (FDA; malignant hyperthermia, muscle spasticity)	yes (NCT02829268)	Normalizing [Ca2+]cyto and calpain activity by inhibiting ER Ca2+efflux via ryanodine receptors [31, 62]
Ibudilast [24]	yes (Japan; asthma, post-stroke dizziness)		Normalizing [Ca2+]cyto [24] through interaction with NCS1 [64] or the cAMP-Ca2+ link [65]
Calpain inhibitor [24]	no		Normalizing calpain activity and [Ca2+]cyto [24]
Pioglitazone [51]	yes (FDA; diabetes mellitus T2)		Restoring ER Ca2+ h me stasis by enhancing SERCA levels [33, 69]
Sitagliptin	yes (FDA; diabetes mellitus T2)		Potentially restoring ER Ca2+ homeostasis [70]
Verapamil	yes (FDA; arrhythmia, angina, hypertension)		Potentially normalizing [Ca2+]cyto and calpain activity by blocking plasma-membrane Ca2+-influx and alleviating ER stress [29, 71, 72]
Targeting ER stress (drug repurposing)
Valproate [77]	yes (FDA; seizures)	yes (NCT03717909)	Alleviating ER stress [75, 76]
GLP1R agonists [78, 79]	yes (FDA; diabetes mellitus T2)		Alleviating ER stress [78, 79]
Stimulating proliferation ( egenerative medicine)
MANF [81]	no		Stimulating proliferation and alleviating ER stress [81]
Akt activators	no		Potentially inducing proliferation and survival by stimulating Akt pathway [80]