A phase 1b/2a clinical trial of dantrolene sodium in patients with Wolfram syndrome

• DOI: 10.1172/jci.insight.145188
• Publication Date: 2021-06-29T16:02:25Z
• Authors: Damien Abreu; Stephen I. Stone; Toni S. Pearson; Robert C. Bucelli; Ashley N. Simpson; Stacy Hurst; Cris M. Brown; Kelly Kries; Chinyere Onwumere; Hongjie Gu; James Hoekel; Lawrence Tychsen; Gregory P. Van St...; Neil H. White; Bess A. Marshall; Tamara Hershey; Fumihiko Urano
• Keywords: Dantrolene Sodium; Wolfram syndrome; Tolerability

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