BACKGROUNDWolfram syndrome is a rare ER disorder characterized by
insulin-dependent diabetes mellitus, optic nerve
atrophy, and progressive neurodegeneration. Although there is no treatment for
Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting ER
calcium homeostasis, including
dantrolene sodium, may be beneficial.METHODSBased on results from preclinical studies on
dantrolene sodium and ongoing longitudinal studies, we assembled what we believe is the first-ever clinical trial in pediatric and adult
Wolfram syndrome patients with an open-label phase Ib/IIa trial design. The primary objective was to assess the safety and tolerability of
dantrolene sodium in adult and pediatric
Wolfram syndrome patients. Secondary objectives were to evaluate the efficacy of
dantrolene sodium on residual pancreatic β cell functions, visual acuity, quality-of-life measures related to vision, and neurological functions.RESULTSDantrolene
sodium was well tolerated by
Wolfram syndrome patients. Overall, β cell functions were not significantly improved, but there was a significant correlation between baseline β cell functions and change in β cell responsiveness (R2, P = 0.004) after 6-month
dantrolene therapy. Visual acuity and neurological functions were not improved by 6-month
dantrolene sodium. Markers of inflammatory
cytokines and oxidative stress, such as IFN-γ, IL-1β, TNF-α, and
isoprostane, were elevated in subjects.CONCLUSIONThis study justifies further investigation into using
dantrolene sodium and other small molecules targeting the ER for treatment of
Wolfram syndrome.TRIAL REGISTRATIONClinicalTrials.gov identifier NCT02829268FUNDINGNIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK112921, DK113487, DK020579), NIH/National Center for Advancing Translational Sciences (NCATS) (TR002065, TR000448), NIH training grant (F30DK111070), Silberman Fund, Ellie White Foundation, Snow Foundation, Unravel
Wolfram Syndrome Fund, Stowe Fund, Eye Hope Foundation, Feiock Fund, Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from NIH/NCATS, Bursky Center for Human Immunology &
Immunotherapy Programs.