September 24th, 2018

Dear Friends,

Thank you so much for your support. I hope you had a nice summer season with your family. I feel that autumn is coming, and it is time for me to update you about our progress. Today, I’d like to talk about one of the new drugs we are developing as we have made significant progress on this drug in the past few months. I call it “Molecular Prosthetics.”

To provide a cure for Wolfram syndrome, we need to stop the disease progression. A common problem in patients with Wolfram syndrome is a particular type of cell stress, endoplasmic reticulum stress (ER stress), caused by the expression of mutant Wolfram protein (WFS1 protein) produced in patients’ cells. ER stress can ultimately result in dysfunction and death of insulin producing cells, retinal cells, and brain cells.  To resolve this issue, we have been developing molecular prostheses that can optimize the structure and conformation of mutant Wolfram protein. If we can restore the structure of mutant Wolfram protein, it should result in resolution of ER stress and reduction of cell death.

I have been working with Amylyx Pharmaceuticals in Cambridge, MA, and NIH/NCATS to evaluate a novel molecular prosthesis in brain cells derived from induced-pluripotent stem cells (iPSCs) of patients with Wolfram syndrome to determine whether this therapeutic has potential to act as a molecular prosthetic/ER stress reducer to treat the disease. We have been getting encouraging results using cells from patients. My goal is to confirm the results in our humanized mouse and rat models of Wolfram syndrome for conducting a clinical trial. This drug seems to be especially beneficial for brain cells. So it is important for us to know if this drug can improve visual acuity and motor function in our rodent models of Wolfram syndrome.

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. Your encouragement keeps me going. I think about our patients every single day. We will decrease human suffering together.

With passion, hope, and gratitude,

Fumi Urano

August 9, 2018

Dear Friends,

I’d like to begin by thanking all of you for your continued support, trust, and faith in me. I always feel your support and energy. It is always my pleasure to update you about our progress. 

To achieve a cure for Wolfram syndrome, we need breakthrough treatments. We currently have three new candidate drugs that can potentially delay or halt the progression of Wolfram syndrome. In parallel, we are developing regenerative gene therapy to protect and regrow remaining eye and brain cells. We usually test the efficacy of candidate drugs and gene therapies in cell models of Wolfram syndrome first. Wolfram cell models are cells derived from our patients or cells lacking normal Wolfram syndrome 1 gene. These cells are sensitive to cell stress and susceptible to cell death. So we are looking for candidate drugs and gene therapies that can reduce cell stress and cell death in Wolfram cell models. The advantage of using cell models is that we can test multiple drug candidates at the same time within a few months. As a next step, we use a mouse model of Wolfram syndrome to test the efficacy of new treatments on visual acuity, brain function, and diabetes. These are genetically engineered mice that do not have Wolfram syndrome 1 gene and develop diabetes, visual impairment, and brain dysfunction. Although these mice are quite useful, it is challenging to test the efficacy of a type of gene therapy called gene editing because they don’t carry abnormal Wolfram syndrome 1 gene variants that our patients carry. In addition, because mice are so small, it is challenging for us to test the efficacy of new treatments in their eyes. Their eyes are so small. To overcome these challenges, I have designed mice and rats carrying Wolfram syndrome 1 gene variants that our patients carry. We call them humanized Wolfram mice and rats. If successful, we can test our new gene therapy and assess the efficacy of new treatments on visual acuity in these humanized Wolfram mice and rats. This will accelerate the pace of our therapeutic development. 

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. I cannot thank you enough.

With passion, hope, and gratitude,

Fumi Urano

June 28, 2018

Dear Friends and Supporters,

It is nice to see you again. I always appreciate your support, trust, and faith in me. I see patients with Wolfram syndrome every week and receive phone calls and emails from patients and their families every single day. It is definitely urgent to slow the progression of the disease and develop novel treatments for achieving a cure.

I attended two important meetings in the past two weeks. From June 11th to June 12th, I attended the International Wolfram Syndrome Workshop in Paris, France, hosted by the French Wolfram Syndrome Association. I attended the first workshop in 2009 together with just 11 other researchers from all over the world. I was the only researcher from the US then. At the first workshop, we agreed to create patient registries and research & service clinics for future clinical trials. As of today, these goals have been achieved, and two drug-repurposing clinical trials are ongoing (https://wolframsyndrome.dom.wustl.edu/clinical-trials/). I met with late Dr. Alan Permutt from Washington University and Mrs. Stephanie Snow Gebel who founded the Snow Foundation at the workshop in 2010, which made me decide to move to Washington University in 2012. At this year’s workshop, almost 50 researchers attended and presented their progress. I presented our progress on our clinical trial and gene therapy strategies. My colleague, Dr. Tammy Hershey, presented MRI findings in patients with Wolfram syndrome. My long-term collaborator, Dr. Tim Barrett in the UK, presented his progress on their clinical trial. I met with multiple collaborators and saw representatives of patient organizations from US, UK, Italy, Spain, Belgium, and France. I was glad to see that the International Wolfram research group had grown. I was glad that all the researchers had been collaborative. I was grateful for everything patient organizations had done for our patients and families, doctors, and researchers.

On Monday, June 25th, I presented my concept of Wolfram spectrum disorder at the American Diabetes Associationmeeting in Orlando, Florida. I believe there are at least three different types of clinical manifestations in Wolfram syndrome and Wolfram-like disorder: mild, intermediate, and severe. I have been developing genetic testing to further understand the spectrum of Wolfram syndrome. Some of our new treatments could be beneficial for patients with all three types in theory. We also need to develop specific treatments for each type.

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. Good things happen to people who do good things.

With passion, unity and gratitude,

Fumi Urano