March 1, 2021

I wish and pray that 2021 is a year of splendid health and big success for you. Despite all the uncertainty, troubles, and challenges on our planet, I have focused my mind and efforts on helping and saving our patients with Wolfram syndrome and WFS1-related disorders. I have been adhering to my three guiding principles: 1. Improve clinical care, 2. Raise awareness, and 3. Provide a cutting-edge treatment for Wolfram syndrome. 

I wanted to write this blog for you because we have exciting updates. 

A Drug-Repurposing Clinical Trial of Dantrolene Sodium 

Nineteen patients completed the required six-month phase, and many of them decided to stay on dantrolene sodium another 18 months. You can find the results of this open-label clinical trial here. In short, the results show that patients with Wolfram syndrome were well tolerated with dantrolene sodium. Although the study was small, a select few patients seemed to have improvements in diabetes-related outcomes, which might correlate with a positive trend in other outcome measures, including visual acuity and brain functions. Dantrolene sodium appears to have multiple targets in addition to the endoplasmic reticulum, a therapeutic target of Wolfram syndrome. Thus, we need second-generation dantrolene, which would be a more specific regulator for the endoplasmic reticulum. Because dantrolene sodium is not a specific regulator, we probably need to increase the dose of dantrolene to make it more effective, especially for patients who have severe manifestations. However, dantrolene sodium may cause liver damage if we increase the dose. We may still use it for patients who have milder symptoms, and this should be investigated further. 

An Upcoming Trial 

A repurposed drug could be just a sticking plaster for Wolfram. So, as you can imagine, we need cutting-edge treatments designed explicitly for Wolfram syndrome. We are currently focusing our efforts on developing AMX0035 with Amylyx in Cambridge, MA, USA, to treat Wolfram syndrome. The targets of AMX0035 are the endoplasmic reticulum and mitochondria. A recent clinical trial of AMX0035 in patients with ALS was a success, and pre-clinical data using induced pluripotent stem cells (iPSCs)-derived brain cells of Wolfram syndrome was positive. Thus, US FDA has granted an orphan drug designation of AMX0035 for the treatment of Wolfram syndrome. I have learned a lot from Prof. Barrett’s clinical trial in Europe and Dr. Hershey’s research clinic in St. Louis to design a new trial for AMX0035, and we are aiming at a multi- center international trial of AMX0035 for Wolfram syndrome. The trial with AMX0035 is a significant development. Please stay tuned. 

Regenerative Gene Therapy 

Our ultimate goal is to provide a cure by regenerative gene therapy. We have been trying to improve diabetes, visual acuity, and brain functions using viral vectors of a healthy Wolfram gene (WFS1) and a regenerative factor called MANF in mouse and rat models. We are getting encouraging preliminary results and have published two articles recently.

https://www.nature.com/articles/s41374-020-0436-1

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233417/ 

We are currently testing the efficacy of AAV-MANF on optic nerve atrophy in rodent models of Wolfram. We hope to update you on this soon. 

Base Editing Gene Therapy 

We have been working with Dr. David Liu’s team at Harvard University/Broad Institute and Dr. Catherine Verfaillie and Dr. Lieve Moons’ teams at the Katholieke Universiteit Leuven to develop a novel gene therapy called Base Editing. This technology uses some components from CRISPR systems together with other enzymes to directly replace abnormal WFS1 gene with normal WFS1 gene. Although we are still at the early preclinical stage using cell models of Wolfram, we hope that we can bring this technology to our patients in the next 3-10 years. We are getting encouraging pre-clinical data using iPSC models. 

New Genetics Clinic is up and running. 

To improve the clinical care for patients with Wolfram syndrome and Wolfram-related disorders, I created a new genetics clinic at the Centre for Advanced Medicine, Washington University Medical Centre. We offer genetic evaluations, education, and counseling for patients and family members of all ages with or suspected to have Wolfram syndrome or WFS1-related disorders. We also provide personalized management plans based on the type of your gene variants together with other specialists at our medical centre, such as Dr. Marshall. Wolfram syndrome Research Alliance and the Snow Foundation have been referring patients to us (https://wolframsyndrome.wustl.edu/). We accept international patients. Please call +1-314- 747-7300 to make an appointment. 

As always, please feel free to contact me with any questions (urano@wustl.edu). I would like to know what you think and how you feel. Thank you for your faith in my work. We will work as one team and make a difference together. 

Sincerely,
Fumi Urano, MD, PhD
Samuel E. Schechter Professor of Medicine Attending physician at Barnes Jewish Hospital Washington University School of Medicine 

To further improve the clinical care for patients with Wolfram syndrome and Wolfram-related disorders, I have created a new genetics clinic at Center for Advanced Medicine, Washington University Medical Center. We offer genetic evaluations, education, and counseling for patients and family members of all ages with or suspected to have Wolfram syndrome or WFS1-related
disorders. We also provide personalized management plans based on the type of your gene variants together with other specialists at our medical center, such as Dr. Marshall, Dr. White, Dr. Hoekel, and beyond. To make an appointment with me, please call 314-747-7300 or 314-747-3294 (if you are participating in our research clinic/registry or interested in participating in the research). You can also send an email to WolframSyndrome@wustl.edu.

We could cover the costs for genetic testing if your insurance does not cover the entire amount of the costs.

Dear Friends,

First of all, I want to express my gratitude for everything you’ve helped me achieve. Your kind words and encouragement keep me motivated and inspired.  I pray you and your family are healthy and in good spirits. I have no doubt better days are ahead, and we can rise about this crisis.

My three guiding principles are: Improve clinical care, Raise awareness, and Provide a cutting-edge treatment for Wolfram syndrome.

Here is our progress:

A Drug-Repurposing Clinical Trial

Our drug-repurposing clinical trial of dantrolene sodium in patients with Wolfram syndrome has been almost concluded. Nineteen patients could successfully complete the required six-month phase, and many of them decided to stay on dantrolene sodium another 18 months. The results of this open-label clinical trial (all the participants took dantrolene sodium) show that dantrolene sodium is well tolerated by patients with Wolfram syndrome. Although the study was small, a select few patients seemed to have improvements in diabetes-related outcomes, which might correlate with a positive trend in other outcome measures, including visual acuity and brain functions. This study justifies further investigation into using dantrolene sodium and other new drugs targeting the same molecular pathway for the treatment of Wolfram syndrome.

Novel Drugs

We are aware that a drug-repurposing is not the best approach to halt the progression of Wolfram syndrome. We need cutting-edge treatments designed explicitly for Wolfram syndrome. Based on the clinical trial data of dantrolene sodium in patients with Wolfram syndrome, we have been actively developing novel drugs in collaboration with the drug development team at the National Institutes of Health (NIH)/National Center for Advancing Translational Sciences in the United States and a few biotech companies. We are currently focusing our efforts on developing AMX0035 together with Amylyx in Cambridge, MA, and ibudilast together with Professor Ehrlich at Yale University.

Regenerative Gene Therapy

My current focus is to develop gene therapy for Wolfram syndrome. Our ultimate goal is to provide a cure using regenerative gene therapy. We have been trying to improve diabetes, visual acuity, and brain functions using viral vectors of a healthy Wolfram gene and a regenerative factor called MANF in mouse models. We are getting encouraging preliminary results and have published two articles recently. We are currently testing two ways to deliver genes through intravitreal (for optic nerve) and intraventricular (for brain) injections.

Base Editing Gene Therapy

In collaboration with Dr. David Liu’s team at Harvard University/Broad Institute and Dr. Catherine Verfaillie’s team at the Katholieke Universiteit Leuven, we have been developing a novel gene therapy called Base Editing for Wolfram syndrome. This technology uses some components from CRISPR systems together with other enzymes to directly replace abnormal WFS1 gene with normal WFS1 gene. Although we are still at the early preclinical stage using cell models of Wolfram, we hope that we can bring this technology to our patients in the next 3-10 years. Please stay tuned.

New Genetics Clinic

To further improve the clinical care for patients with Wolfram syndrome and Wolfram-related disorders, I have created a new genetics clinic at Center for Advanced Medicine, Washington University Medical Center. We offer genetic evaluations, education, and counseling for patients and family members of all ages with or suspected to have Wolfram syndrome or WFS1-related disorders. We also provide personalized management plans based on the type of your gene variants together with other specialists at our medical center, such as Dr. Marshall, Dr. White, Dr. Hoekel, and beyond. To make an appointment with me, please call 314-747-7300 or 314-747-3294 (if you are participating in our research clinic/registry or interested in participating in the research). You can also send an email to WolframSyndrome@wustl.edu. We could cover the costs for genetic testing if your insurance does not cover the entire amount of the costs.

Finally, I want to express my gratitude to Dr. Hershey, Dr. Marshall, Mrs. Samantha Blankenship, Dr. White, and other physicians and scientists for running the Wolfram research clinic study, Mrs. Cris Brown and Mrs. Stacy Hurst for managing the Wolfram registry and clinical study, scientists in my lab, collaborators all over the world, including Dr. Barrett, Dr. Plaas, Dr. Terasmaa, Dr. Millman, Dr. Ehrlich, and supporters for my research.

As always, please feel free to contact me with any questions (urano@wustl.edu). I would like to know what you think and how you feel. Thank you again for your continued support and encouragement. I have no doubt better days are ahead. We will go through this challenging period with unusual optimism and courage. Thank you, Stephanie Gebel and Snow Foundation. Welcome to the foundation. Pat Gibilisco. We will continue working as one team and change history together.

Sincerely,

Fumi Urano, MD, PhD

January 29, 2020

Dear Friends,

I hope 2020 has been going well for you. Thank you for your email, letters, and messages at the end of last year. I really appreciated your encouragement. I am determined to make 2020 the game-changing year for us. Three things are always on my mind: Improve clinical care, Raise awareness, and Provide a cutting-edge treatment for Wolfram syndrome. I have four goals for 2020.
1. Set up a new clinical trial for Wolfram syndrome using a new drug (more specifically, get an orphan drug designation, create a trial protocol, and secure funds)

2. Complete preclinical studies for gene therapy for optic nerve atrophy in Wolfram (more specifically, complete studies in rodent and iPSC models) and start setting up a clinical study.

3. Start preclinical studies for gene therapy for brain dysfunction in Wolfram syndrome.

4. Set up genetic testing for genetic forms of diabetes and ER stress-related disorders and create a clinical service for those patients.

As always, please feel free to contact me with any questions (urano@wustl.edu). I would like to know what you think and how you feel. Thank you again for your continued support and encouragement. I am determined to make a difference in the future of our patients. We will work as one team and change history together.

Sincerely,
Fumi Urano