The Translating Mechanisms for a Genetic Neurodegenerative Disease into New Therapies: Wolfram Syndrome study is exploring the molecular endoplasmic reticulum (ER) dysfunction mechanisms in Wolfram Syndrome (WS) to identify patient-based therapeutics and actionable targets. Dr. Fumihiko Urano was awarded ICTS pilot and JIT funding in 2011 to establish a clinic for phenotypic characterization of children with WS and to collect and bank patient-derived induced pluripotent stem cells (iPSCs) from patients and family members to uncover biomarkers. Additional funding (ICTS STAR in 2015 and ICTS JIT in 2016) helped support further research and to prepare regulatory documents for a Phase 1b Clinical Trial, which started in January 2017.
Wolfram Syndrome (WS) is a rare inherited condition characterized by juvenile diabetes, optic nerve atrophy, deafness, and neurodegeneration. WS affects one in 500,000 people worldwide and is often fatal by mid-adulthood due to multi-organ health complications.1 The Wolfram Syndrome study confirmed that WS has a pronounced impact on early brain development, accompanied with impairments in gait and balance.
Fumihiko Urano, MD, PhD, Samuel E. Schechter Professor of Medicine
Washington University School of Medicine in St. Louis
Dr. Urano and his team found that endoplasmic reticulum (ER) dysfunction is a critical pathogenic component of Wolfram syndrome. Dantrolene sodium, a drug used to treat muscle spasticity, was identified as a potential therapeutic target as it prevented the destruction of insulin-producing beta cells in mouse models of WS and in cells taken from patients who have the illness.2 Growing evidence indicates that ER dysfunction is involved in other rare genetic disorders and more common diseases such as Type 1 and Type 2 diabetes and Parkinson’s disease, leading to potential advances in therapies for these diseases.
Dr. Urano continues to collaborate with the NIH/NCATS and a biotechnology company, and these ongoing studies include regenerative tissue therapies and the development of molecular prosthetics that can optimize the structure of mutant Wolfram protein.3
Developed a rating scale of disease severity in WS. Wolfram United Rating Scale (WURS). 2012.
Dantrolene sodium assigned Orphan Drug Status for the treatment of Wolfram Syndrome by the U.S. Food and Drug Administration (FDA). February 2016.
Dantrolene sodium assigned Orphan Drug Status for the treatment of Wolfram Syndrome by the European Medicines Agency. December 2016.
Phase 1b clinical trial: “A Clinical Trial of Dantrolene Sodium in Pediatric and Adult Patients With Wolfram Syndrome” started in January 2017. ClinicalTrials.gov Identifier: NCT02829268.
Dantrolene sodium, a drug used to treat muscle spasticity, was identified as a potential therapeutic target. 2014.
Proof of concept demonstration: Gene-editing tools used to correct a diabetes-causing genetic defect in mice. 2020.
WO 2016077706 A1 Patent: Treatment for Wolfram Syndrome and Other Endoplasmic Reticulum Stress Disorders. Filing Date: November 13, 2015. Publication Date: May 19, 2016.
Early benefits of the Wolfram Syndrome study have been observed in two TSBM domains since 2011. In the Clinical & Medical benefits domain, a rating scale for severity of Wolfram Syndrome was published by the Washington University Wolfram Study Group in 2012.4 In 2014, Dantrolene sodium, a drug used to treat muscle spasticity, was identified as a potential therapeutic target as research found that the drug prevented insulin-producing beta cells in human and rodent cell models, as well as mouse models of Wolfram Syndrome.5 Orphan disease designation was assigned to Dantrolene sodium for the treatment of Wolfram Syndrome by the U. S. Food and Drug Administration (FDA),6 followed by the European Medicines Agency.7
A Phase 1b Clinical trial: “A Clinical Trial of Dantrolene Sodium in Pediatric and Adult Patients With Wolfram Syndrome” started in January 2017.8 The purpose of the Clinical trial Phase 1b is to assess the safety and efficacy of Dantrolene sodium on patients’ vision, brain functions, and diabetes in pediatric and adult WS patients. As of January 2018, there were 19 current participants and the estimated completion date is March 2021. The findings from the Clinical trial as of 2019 suggest that Dantrolene is safe for use in Wolfram syndrome at the specified doses and support further study of Dantrolene in a randomized, placebo-controlled trial.9
In the Economic benefits domain, a patent, “Treatment for Wolfram Syndrome and Other Endoplasmic Reticulum Stress Disorders” was filed in 2015 and granted in October 2019 (US10441574B2).10
The patient-derived induced pluripotent stems cells (iPSCs) collected and banked as part of Dr. Urano’s ICTS-funded work have enabled new collaborations and another potential therapy for Wolfram Syndrome. Dr. Jeffrey Millman and his team collaborated with Dr. Urano. They used the gene-editing tool CRISPR-Cas9 to correct the genetic defect that causes Wolfram syndrome and then transformed the human stem cells into pancreatic beta cells, using a technique developed by Dr. Millman and colleagues. The beta cells were then implanted into lab mice which cured unrelenting diabetes in mice.
“We basically were able to use these cells to cure the problem, making normal beta cells by correcting this mutation…It’s a proof of concept demonstrating that by correcting gene defects that cause or contribute to diabetes—in this case, in the Wolfram syndrome gene—we can make beta cells that more effectively control blood sugar. It’s also possible that by correcting the genetic defects in these cells, we may correct other problems that Wolfram syndrome patients experience, such as visual impairment and neurodegeneration.”11Dr. Urano
- Urano F. Wolfram Syndrome: Diagnosis, management, and treatment. Curr Diab Rep (2016) 16: 6.
- Lu S, Kanekura K, Hara T, et al. A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome. Proc Natl Acad Sci U S A. 2014 Dec 9;111(49):E5292-301.
- Urano F. CURE4WOLFRAM 4.0. Dr. Urano’s Blog. March 13, 2018.
- Nguyen C, Foster ER, Paciorkowski AR, et al. Reliability and validity of the Wolfram Unified Rating Scale (WURS). Orphanet J Rare Dis. 2012 Nov 14;7:89. doi: 10.1186/1750-1172-7-89.
- Lu S, Kanekura K, Hara T, et al. A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome. Proc Natl Acad Sci U S A. 2014 Dec 9;111(49):E5292-301. doi: 10.1073/pnas.1421055111.
- U.S. Food and Drug Administration. Orphan Drug Designations and Approvals. Dantrolene Sodium Orphan Drug Designation for Treatment of Wolfram Syndrome. February 17, 2016. Available from: https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=474515.
- European Medicines Agency. Public summary of opinion on orphan designation. EU/3/16/1800. December 12, 2016. Available from: https://www.ema.europa.eu/medicines/human/orphan-designations/eu3161800.
- A Clinical Trial of Dantrolene Sodium in Pediatric and Adult Patients With Wolfram Syndrome. ClinicalTrials.gov Identifier: NCT02829268. ClinicalTrials.gov. Available from: https://clinicaltrials.gov/ct2/show/NCT02829268.
- Abreu D, Pearson TS, Bocelli RC, Simpson A, Brown CM, Kries K, Gu H, Stone SI, Tychsen L, Van Stavern G, White NH, Marshall BA, Hershey T, Urano F. 85-LB: A Phase 1b/2 clinical trial of Dantrolene Sodium in patients with Wolfram Syndrome. Diabetes 2019 Jun; 68(Supplement 1). Available from: https://doi.org/10.2337/db19-85-LB.
- UranoF. & Lu S., inventors; Washington University, assignee. Treatment for Wolfram Syndrome and other endoplasmic reticulum stress disorders. United States patent US 10,441,574. 2019.
- Dryden, J. Diabetes reversed in mice with genetically edited stem cells derived from patients. The Source. April 22, 2020. Available from: https://source.wustl.edu/2020/04/diabetes-reversed-in-mice-with-genetically-edited-stem-cells-derived-from-patients/.