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.
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.
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
Dear Friends,
I hope you and your family are safe and well during this COVID-19 pandemic. Three things are always on my mind: Improve clinical care, Raise awareness, and Provide a cutting-edge treatment for Wolfram syndrome. As I mentioned on January 1st, I am determined to make 2020 the game-changing year for us despite this challenging time. Today, I would like to share the good news with you.
We have been testing if gene editing by CRISPR-Cas9, in combination with patient-derived induced pluripotent stem cells (iPSCs), can be utilized for the treatment of Wolfram Syndrome.I am glad to inform you that gene editing worked in Wolfram patient iPSC-derived beta cells. We were able to use these cells to cure one of the problems, making normal beta cells by correcting WFS1 gene mutation. We could cure diabetes in cells and mice. This is a proof of concept demonstrating that correcting gene defects that cause or contribute to medical problems— in this case, in the Wolfram syndrome gene — we can cure the problems. This is a major discovery in the gene therapy field, and it has been just published in a high-profile medical research journal, Science Translational Medicine.https://medicine.wustl.edu/news/diabetes-reversed-in-mice-with-genetically-edited-patient-derived-stem-cells/
Based on this discovery, it is now possible that by correcting the genetic defects in these cells, we may correct other problems Wolfram Syndrome patients experience, such as visual impairment and neurodegeneration. So, we are currently working on eye and brain cells derived from iPSCs of patients with Wolfram Syndrome to replicate this success for other problems. Many, many thanks to my patients, colleagues at Washington University and supporters in the world. Thank you, Stephanie Snow Gebel and the Snow Foundation.
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, especially in this very trying time, not only for our country, but the world. We will work as one team and change history together.
“That’s one small step for us today, leading to one giant leap toward a cure for Wolfram Syndrome.”
Sincerely,
Fumi Urano, MD, PhD
April 23, 2020
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
October 13, 2019
Dear Friends,
It is wonderful to see you. I always appreciate your continued support and encouragement. I have been doing my best to develop cutting-edge treatments for Wolfram syndrome and save our patients. It has been tough, but your kind words keep me going. I feel incredibly grateful. I would like to share our progress and ideas.
As you know, our clinical trial of dantrolene sodium for adult and pediatric patients with Wolfram syndrome has been going well, but a mild success. To improve the efficacy of dugs targeting endoplasmic reticulum stress (ER stress: a molecular mechanism of Wolfram syndrome), I have been working on two new drugs targeting ER stress. Based on the results of dantrolene trial, I am confident that targeting ER stress is beneficial for patients with Wolfram syndrome. Preclinical data (i.e., data using cell and animal models) and safety profile of both new drugs look very good. Thus, I am planning a multi-center trial using one of these drugs. My goal is to make this happen in the next 12-24 months. I will do my best.
Another priority for me is to develop gene therapy for vision impairment in Wolfram syndrome. We have created adeno-associated virus (AAV: a safe virus utilized for gene therapy) that can deliver normal Wolfram gene (WFS1) and a regeneration factor, MANF, into retinal cells. We got an encouraging result last week showing that one of our new type of viruses can deliver MANF into retinal ganglion cells efficiently in a mouse model of Wolfram syndrome. My goal is to complete preclinical studies on gene therapy as quickly as possible. This is always on my mind. I will keep on doing my best and keep you updated. I am assembling a strong team of eye doctors.
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 continued support. We will decrease human suffering and change the future of our patients together.
With gratitude,
Fumi Urano
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
October 18, 2018
Dear Friends,
It is wonderful to see you again. I hope you and your family are enjoying the beautiful autumn weather and nature. I love to do a nature walk especially in autumn, and I came up with the following idea during my nature walk. I’d like to share this idea with you as I know you are my friend and supporter.
To provide a cure for Wolfram syndrome, we need to protect our eye cells, brain cells, and insulin producing cells. If they are damaged, we need to fix them and even regenerate them. I came up with the concept of “Regenerative Gene Therapy.” This is a combination of regenerative therapy and gene therapy. As you know, my team has discovered a molecule that is produced naturally in the body that can activate the proliferation of damaged beta cells and brain cells. Expression levels of this molecule, MANF, are usually low in the human body. We are developing a method to enhance the activity of MANF using a gene therapy. We are trying to produce a safe virus expressing MANF to transduce into patients’ cells with resultant creation of MANF within the cell. This treatment could then be applicable to Wolfram syndrome, as well as other forms of neurodegenerative disease.
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. I always appreciate your support and encouragement. You are a wonderful person. We will decrease human suffering together.
With gratitude,
Fumi Urano
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
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