Dear Friends,

The spring has come and the winter has gone. I experienced so many challenging events and incidents during the past winter season, and I feel that we hit the bottom and things have started to move up in the right direction.  Your kind words and encouragement are the engine for my quest to a cure for Wolfram syndrome. It is my pleasure to tell you about our ongoing clinical trial and therapeutic strategies.

A Drug-Repurposing Clinical Trial

Our drug-repurposing clinical trial of dantrolene sodium in patients with Wolfram syndrome is still ongoing. 19 patients could successfully complete the required 6-month phase, and many of them have decided to stay on dantrolene sodium another 18 months. We have determined the appropriate doses for adult and pediatric patients and started seeing encouraging results in their remaining beta cell functions. As this is an open-label study, we cannot conclude that these encouraging results are due to dantrolene sodium. We plan to continue this study until the end of 2019 and move on to the next step.

Because dantrolene sodium was not specifically designed to treat Wolfram syndrome, it may not be optimally suited to address all aspects of Wolfram syndrome pathophysiology. We have been developing novel drugs (endoplasmic reticulum calcium stabilizers) for the treatment of Wolfram syndrome together with a drug development team at the National Institutes of Health. Our new drug candidate seems be safer, more potent and goes to the brain and eyes more efficiently than dantrolene sodium. We are testing this candidate drug in brain cells differentiated from induced pluripotent stem cells (iPSCs) derived from our patients and plan to conduct further studies in humanized Wolfram mice and rats.

Molecular Prosthetics

Another common molecular issue in patients with Wolfram syndrome is cellular stress caused by the expression of mutant Wolfram (WFS1) proteins derived from mutant Wolfram gene (WFS1) variants. To resolve this issue, we have been developing a molecular prosthesis that can optimize the structure of mutant Wolfram protein together with a biotech company in the US. Molecular prosthetics are drugs that can get into the cells and correct the abnormal structure of mutant Wolfram protein in patients’ cells. 

Regenerative Gene Therapy

Our ultimate goal is to provide a cure using regenerative gene therapy. We have been trying to improve visual acuity and brain functions using safe virus expressing healthy Wolfram gene (WFS1) and a regenerative factor called MANF in a rodent model of Wolfram syndrome. In parallel, we are attempting to replace a pathogenic Wolfram gene with a healthy Wolfram gene using a gene editing technology (CRISPR/CAS9).  This work is currently being done using induced pluripotential stem cells (iPSCs) generated for study of treatments for Wolfram syndrome.  

Humanized Wolfram Rats and Mice

To test these cutting-edge therapies, especially gene therapy, we need animal models carrying human Wolfram gene mutations. We have successfully created rats and mice carrying human Wolfram gene mutations. We have started characterizing these animals to assess the efficacy of new treatments. 

As always, please feel free to contact me with any questions or concerns (urano@wustl.edu). I would like to know what you think and how you feel. Thank you again for your support. We will decrease human suffering together.

With passion and gratitude,

Fumihiko “Fumi” URANO, MD, PhD

Professor of Medicine and Pathology, Samuel E Schechter Endowed Chair
Barnes-Jewish Hospital/Saint Louis Children’s Hospital
Washington University School of Medicine