TY - JOUR
T1 - A phase Ib/IIa clinical trial of dantrolene sodium in patients with Wolfram syndrome
AU - Abreu, Damien
AU - Stone, Stephen I.
AU - Pearson, Toni S.
AU - Bucelli, Robert C.
AU - Simpson, Ashley N.
AU - Hurst, Stacy
AU - Brown, Cris M.
AU - Kries, Kelly
AU - Onwumere, Chinyere
AU - Gu, Hongjie
AU - Hoekel, James
AU - Tychsen, Lawrence
AU - van Stavern, Gregory P.
AU - White, Neil H.
AU - Marshall, Bess A.
AU - Hershey, Tamara
AU - Urano, Fumihiko
N1 - Funding Information:
FUNDING. NIH/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.
Funding Information:
research funding from Eli Lilly, Ono Pharmaceuticals, and Amarantus BioScience for the development of MANF-based regenerative therapy for Wolfram syndrome, optic nerve atrophy, and diabetes. FU received chemical compounds from Amylyx Pharmaceuticals, Mitochon Pharmaceuticals, and Aetas Pharma, and for the development of small molecule–based therapies for ER stress–related disorders, including Wolfram syndrome. FU is an inventor of 2 patents related to the treatment of Wolfram syndrome, US 9,891,231 Soluble MANF in Pancreatic Beta Cell Disorders and US 10,441,574 and US 10,695,324 Treatment for Wolfram Syndrome and Other ER Stress Disorders. FU is a founder and president of CURE4WOLFRAM, Inc.
Funding Information:
Inflammatory cytokine levels were analyzed in the Immunomonitoring Laboratory Core Lab. F2-isoprostanes were analyzed in the Eicosanoid Core Laboratory at Vanderbilt University Medical Center, and we are thankful for the feedback from Diane Bender, Ginger Milne, and John Geisler regarding these biomarkers. The authors thank all the members of the Washington University Wolfram Syndrome Study and Research Clinic for their support (https://wolframsyndrome.wustl.edu) and all the participants in the Wolfram Syndrome International Registry and Clinical Study, Research Clinic, and Clinical Trials for their time and efforts. DA was supported by the NIH training grant (F30DK111070). This work was partly supported by grants from the NIH/NIDDK (DK112921, DK113487, DK020579) and NIH/NCATS (TR002065, TR000448) and philanthropic supports from the Silberman Fund, the Ellie White Foundation, the Snow Foundation, the Unravel Wolfram Syndrome Fund, the Stowe Fund, the Eye Hope Foundation, and the Feiock Fund to FU. Research reported in this publication was also supported, in part, by the Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from the NIH/NCATS and by the Bursky Center for Human Immunology & Immunotherapy Programs at Washington University Immunomonitoring Laboratory. The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH.
Publisher Copyright:
Copyright: © 2021, Abreu et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2021/8/9
Y1 - 2021/8/9
N2 - BACKGROUND. Wolfram 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. METHODS. Based 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. RESULTS. Dantrolene 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. CONCLUSION. This study justifies further investigation into using dantrolene sodium and other small molecules targeting the ER for treatment of Wolfram syndrome.
AB - BACKGROUND. Wolfram 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. METHODS. Based 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. RESULTS. Dantrolene 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. CONCLUSION. This study justifies further investigation into using dantrolene sodium and other small molecules targeting the ER for treatment of Wolfram syndrome.
UR - http://www.scopus.com/inward/record.url?scp=85112293912&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.145188
DO - 10.1172/jci.insight.145188
M3 - Article
C2 - 34185708
AN - SCOPUS:85112293912
VL - 6
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 15
M1 - e145188
ER -