,

Groundbreaking research of Dr. Fumihiko Urano at Washington University School of Medicine, USA

Dr. Fumihiko Urano Washington University School of Medicine, USA

Dr. Fumihiko Urano

Washington University School of Medicine, USA

Dear Friends,

 

I want to take a moment to express my deep gratitude for your unwavering belief in and support of our mission to find a cure for Wolfram syndrome. Your enduring encouragement has been a beacon of hope guiding us on this remarkable journey. As we embark on the year 2024, filled with hope and determination to inch closer to our goal of finding a cure, I would like to provide a summary of our progress in the battle against Wolfram syndrome.

 

Rare Disease Day at NIH 2024

Before I delve into our progress update, I’m excited to share some fantastic news with you. I’ve received an invitation to present our research on Wolfram Syndrome at the Rare Disease Day event held at the National Institutes of Health on February 29, 2024. This event is widely regarded as one of the most prestigious gatherings for rare diseases, offering an excellent platform for us to raise awareness about Wolfram Syndrome. Even if you can’t attend in person, you can still participate by watching my presentation remotely. Here is the link to access it: https://ncats.nih.gov/news-events/events/rdd

 

Ongoing clinical trial

In partnership with Amylyx Pharmaceuticals, we are actively advancing the development of AMX0035, an innovative oral medication designed to slow or halt the progression of Wolfram syndrome. In 2020, the US FDA granted AMX0035 orphan drug status for Wolfram syndrome. Using data from previous clinical studies, we have developed a protocol to assess the safety and effectiveness of AMX0035. This protocol has been approved by both the US FDA and the Institutional Review Board at Washington University Medical Center. We have initiated a phase 2 clinical trial for adult patients with Wolfram syndrome at Washington University Medical Center, with the first participant starting AMX0035 treatment in April 2023.

 

Our trial is proceeding smoothly, and we are currently planning our next steps. We have received numerous inquiries about including children in the trial, as well as patients without diabetes and patients with WFS1-related disorders (those who have hearing loss and optic nerve atrophy due to having one pathogenic copy of WFS1). We appreciate your interest and feedback, and we plan to make a formal announcement later this year. Please stay tuned for further updates.

 

Regenerative Therapy for Optic Nerve Atrophy

Our primary objective is to halt and reverse the progression of low vision resulting from optic nerve atrophy in individuals with Wolfram syndrome. We are pursuing this goal through regenerative medicine. Our current strategy involves the administration of a regenerative factor called MANF into the eyes of Wolfram syndrome patients using a viral vector. As you may be aware, our brain naturally produces certain neurotrophic factors like BDNF and CDNF to maintain brain health. MANF is also a neurotrophic factor, but it stands out because it offers protection against Endoplasmic Reticulum (ER) stress, a key molecular mechanism involved in Wolfram syndrome. Additionally, MANF aids in boosting the growth of ER-stressed cells. We are presently conducting preclinical studies using cell and rodent models specifically designed to mimic Wolfram syndrome, in order to evaluate the effectiveness of MANF in addressing optic nerve atrophy. Promising results have emerged from our humanized mouse model of Wolfram syndrome, indicating the potential of this innovative approach to treat other causes of low vision as well. While there are undoubtedly several challenges ahead, our ultimate aim is to initiate a regenerative therapy trial for optic nerve atrophy within the next 3 to 7 years.

 

Gene Editing Therapy

The primary cause of Wolfram syndrome stems from a pathogenic alteration within the WFS1 gene. Consequently, the most effective approach to treating Wolfram syndrome involves rectifying these gene mutations. To ensure safety, we have transitioned from using CRISPR to utilizing the more advanced Base Editing (2nd generation) and Prime Editing (3rd generation) techniques to correct the pathogenic changes in the WFS1 gene associated with Wolfram syndrome. These cutting-edge gene editing technologies are currently considered the most advanced methods available. To evaluate the efficacy of this technology, we have generated rodent models featuring pathogenic mutations in the Wfs1 gene that closely mimic those observed in our patients. Our ultimate objective is to apply this therapeutic approach to benefit our patients within the next 5-10 years.

 

International Consortium

I’d like to present a significant idea to you. After extensive thought and discussions with senior advisers, I’ve made the decision to establish an international consortium focused on Wolfram Syndrome and Related Disorders and join the Rare Diseases Clinical Research Network (https://www.rarediseasesnetwork.org/). I intend to submit a substantial grant application to the National Institutes of Health. Through this consortium, my goals are as follows. I’m pleased to share that The Snow Foundation has graciously agreed to lead the patient organization group for objective #4.

1. Advance our understanding of the clinical manifestations of Wolfram syndrome and related disorders through collaborative clinical research.

2. Collaboratively create thorough clinical guidelines.

3. Investigate genotype-phenotype correlations and identify drug targets.

4. Improve awareness among scientists, physicians, and the general public regarding the unique needs of patients with Wolfram syndrome and related disorders with patient organizations.

 

Clinical service

To improve the clinical care for patients with Wolfram syndrome and WFS1-related disorders, including WFS1-related deafness and optic nerve atrophy, we have been running the WFS1 clinic at the Center for Advanced Medicine, Washington University Medical Center. This clinic has been successful, and I see patients from different states and countries almost every week. I appreciate that the Snow Foundation, the Ellie White Foundation, the Unravel Wolfram Syndrome, and the FB groups related to Wolfram syndrome have referred patients to our clinic. We offer genetic evaluations, education, and counseling for patients and family members of all ages with or suspected to have Wolfram syndrome and WFS1-related disorders. We also provide personalized management plans with other specialists at our medical center and beyond. We accept international patients via our international patient care office. We also accept out-of-state patients.

 

Patients in the US

If you’re in the US, please call Christine Manning, RN, Nurse Coordinator, at 314-747-7055 or 314-362-3500. Let her know that you or your family member has Wolfram syndrome or WFS1-related medical conditions and need to make an appointment. Once we review your medical records, Dr. Urano or his staff will contact you to discuss which specialists you may need to see.

 

Sending Medical Records via Fax

Please fax your medical records to 314-747-7065.

 

Referrals via Fax for both Missouri patients and out-of-state patients

Please fax your referral request to 314-747-7065.

 

International Patients

International patients are welcome to contact our international patient care office to schedule an appointment by calling +1-314-273-3780 or sending an email to Internationalpatients@wustl.edu.

 

Conclusion

The encouraging outcomes we’ve witnessed fill us with hope for the future, and we’re dedicated to forging ahead in our mission to bring about meaningful change. Thank you again for your unwavering support. Together, we will persist in our efforts and shine a beacon of hope for those affected by Wolfram syndrome. Here’s to a brighter future on the horizon!

 

With grace and gratitude,

Fumi

 

Fumihiko Urano, MD, PhD, FACMG

Professor of Medicine and of Pathology & Immunology

Samuel E. Schechter Endowed Professor in Medicine

Director, Wolfram Syndrome/WFS1-related disorders Registry & Clinical Study and WFS1 clinic at BJC HealthCare

Washington University School of Medicine

https://wolframsyndrome.wustl.edu/

/by
,

Update by Dr. Fumihiko Urano – September 14th

Fumihiko “Fumi” Urano, MDAugust 30, 2023

Dear Friends,

Thank you so much for continually believing in and supporting me. I deeply appreciate it! Your encouragement has been such a driving force in our journey. Excitingly, we’re making significant strides in our therapeutic development for Wolfram syndrome. I can’t wait to fill you in on all the details. Let’s dive right into an update about our current clinical trial.

Ongoing clinical trial

We’re genuinely excited about the positive strides being made in Wolfram syndrome treatments. In collaboration with our partners at Amylyx Pharmaceuticals, we’re actively advancing the development of AMX0035, an innovative oral medication designed to halt the progression of Wolfram syndrome. Interested in understanding how AMX0035 addresses endoplasmic reticulum stress and mitochondrial dysfunction? We invite you to explore our latest article here: https://insight.jci.org/articles/view/156549.

In 2020, the US FDA granted AMX0035 orphan drug status for Wolfram syndrome. Using previous study data, we developed a safety and effectiveness protocol for AMX0035, which has been approved by the US FDA and the Institutional Review Board at Washington University Medical Center:

We’ve started a phase 2 clinical trial for adult Wolfram syndrome patients:

https://wolframsyndrome.wustl.edu/items/a-phase-ii-study-of-safety-and-efficacy-of-amx0035-in- adult-patients-with-wolfram-syndrome/.
Our first participant was dosed in April 2023: https://www.amylyx.com/news/amylyx- pharmaceuticals-announces-first-participant-dosed-in-phase-2-study-of-amx0035-for-the- treatment-of-wolfram-syndrome.

Our trial is progressing smoothly and more patients have been dosed, and we are already mapping out our subsequent steps. Stay tuned for updates.

Gene Editing Therapy

As you are all aware, Wolfram syndrome is a medical condition caused by issues in a gene named WFS1. When this gene isn’t functioning right, it can lead to multiple health problems, including optic nerve atrophy, diabetes mellitus, and neurodegeneration. Our current focus and priority is to safeguard the retinal ganglion cells. Why? Because these cells play a crucial role in preventing damage to the optic nerve and maintaining vision.

To address this, we’ve joined hands with distinguished scientists: Dr. Catherine Verfaillie, Dr. Lies De Groef, and Dr. Lieve Moons from Katholieke Universiteit Leuven in Belgium. Together, we’re applying a pioneering technique named “Base Editing” to make corrections in the problematic gene changes. Using iPS cells derived from Wolfram syndrome patients, we’ve seen promising results with this method. Our next step is to test this approach on a mouse model that simulates the human condition of Wolfram syndrome.

Besides “Base Editing,” we’re diving deep into an even newer method called “Prime Editing.” This is cutting-edge technology in gene correction. For this endeavor, we’re collaborating with Dr. David Liu and his team from Harvard/MIT, who are at the forefront of this field.

Ultimately, our heartfelt goal is to harness these innovative techniques to bring relief to those living with Wolfram syndrome.

Regenerative Therapy for Optic Nerve Atrophy – Gene Therapy and Mesenchymal Stem Cell Transplantation
We’re looking into new ways to heal and even reverse damage to the optic nerve, which is the nerve in our eyes that helps us see. We’ve come up with two main ideas.

First, we’re trying to introduce a special regenerative factor, called MANF, into the eyes of patients with Wolfram syndrome. We use a virus (a safe one!) to help deliver this factor. MANF helps protect retinal ganglion cells and encourages them to grow.

Secondly, we’re testing the use of special cells, called mesenchymal stem cells, which we can get from fat tissues or bone marrow. In previous tests with animals, these cells have been shown to help eye nerve cells survive and grow back after damage.

Right now, we’re doing more tests using MANF in rodent models of Wolfram syndrome developed in our lab. If everything goes well, we hope to test these methods on actual patients in the next 3- 7 years.

Clinical service

At the Washington University Medical Center’s Center for Advanced Medicine, we have established the Wolfram Syndrome and Related Disorders Clinic program, aimed at improving clinical care for patients with Wolfram syndrome and related disorders, including WFS1-related deafness and optic nerve atrophy.

Our program provides genetic evaluations, education, and counseling services to patients and family members of all ages who have either been diagnosed with Wolfram syndrome, are suspected of having it, or have WFS1-related disorders.

Our team collaborates with other specialists, including neurologists, neuro-ophthalmologists, urologists, medical geneticists, and endocrinologists at our medical center, to provide personalized management plans. We strive to see patients either on the same day or within two consecutive days. Our services are available to both pediatric and adult patients.

Patients in the US

If you’re in the US, please call Christine Manning, RN, Nurse Coordinator, at 314-747-7055 or 314-362-3500. Let her know that you or your family member has Wolfram syndrome or WFS1- related medical conditions and need to make an appointment. Once we review your medical records, Dr. Urano or his staff will contact you to discuss which specialists you may need to see.

Sending Medical Records via Fax

Please fax your medical records to 314-747-7065.

Referrals via Fax for both Missouri patients and out-of-state patients

Please fax your referral request to 314-747-7065.

International Patients

International patients are welcome to contact our international patient care office to schedule an appointment by calling +1-314-273-3780 or sending an email to Internationalpatients@wustl.edu.

Conclusion

So many things are happening in the world of Wolfram syndrome. Let’s keep the momentum going! Our team’s dedication to therapeutic development for Wolfram syndrome shines bright, and it’s deeply inspired by the resilience of patients and families facing this condition. The positive results we’re seeing are truly uplifting and fuel our hope for the future. While challenges remain, rest assured, we’re wholeheartedly committed to driving breakthroughs that could transform the lives of those with Wolfram syndrome. Stay tuned for more updates, and a huge thank you for being our rock-solid support!

With grace and gratitude, Fumi

Fumihiko Urano, MD, PhD, FACMG
Professor of Medicine and of Pathology & Immunology
Samuel E. Schechter Endowed Professor in Medicine
Director, Wolfram Syndrome/WFS1-related disorders Registry & Clinical Study and WFS1 clinic at BJC HealthCare
Washington University School of Medicine
https://wolframsyndrome.wustl.edu/

/by

Urano publishes research on the connection between loss of WFS1 function and ER stress-mediated inflammation

Urano publishes research on the connection between loss of WFS1 function and ER stress-mediated inflammation

/by

Dr. Fumihiko Urano’s presentation from Washington University’s Wolfram Syndrome Patient/Family Virtual Clinic

/by

Dr Urano’s September 2021 Update

 

September 25, 2021

 

Dear Friends and Supporters of the Snow Foundation,

I hope you are splendid. Our lab has been 100% functional and welcomed four new research team members in the past three months. So, we are ready to accelerate our progress. I continue adhering to my three guiding principles: 1. Improve clinical care, 2. Raise awareness, and 3. Provide a cutting-edge treatment for Wolfram syndrome. Here are our updates.

An Upcoming Trial

We just published the data of our drug-repurposing trial using dantrolene sodium in the Journal of Clinical Investigation Insight (https://insight.jci.org/articles/view/145188). This is an open-access article, and anyone can read it at no cost. Although the results were not what we had hoped, I learned a lot from this trial, which will help us design a new trial. As I repeatedly mentioned in the past, a repurposed drug could be just a band-aid for Wolfram. So, we need a new medication designed explicitly for Wolfram syndrome. 

As you know, we have been focusing our efforts on developing AMX0035 for the treatment of Wolfram syndrome with Amylyx in Cambridge, Massachusetts, in the US. AMX0035 targets endoplasmic reticulum stress (a molecular mechanism of Wolfram) and mitochondria dysfunction. A recent clinical trial of AMX0035 in patients with ALS, an adult-onset neurodegenerative disorder, was successful (https://www.nytimes.com/2020/10/16/health/ALS-treatment.html). Our pre-clinical data using induced pluripotent stem cells (iPSCs)-derived brain cells of Wolfram syndrome and Wolfram mice were positive, and we plan to publish the data soon. US FDA granted an orphan drug designation of AMX0035 for the treatment of Wolfram syndrome in October 2020. We submitted our clinical trial plan to the US FDA late May, 2021, and received their feedback late July, 2021. We are revising our trial protocol to ensure the safety of our patients and assess the efficacy of AMX0035 accurately. I spend certain amount of time every single day on this together with medical officers at Amylyx and my colleagues at Washington University. We are making steady progress to start this trial.

Our clinical trial of AMX0035 in patients with Wolfram syndrome has been designed based on Dr. Barrett’s clinical trial design in Europe, Dr. Hershey’s research clinic data in St. Louis, and our dantrolene trial design and data in St. Louis. I have been closely working with Dr. Patrick Yeramian, Dr. Jüergen Reess  and Dr. Jamie Timmons at Amylyx and Dr. Tamara Hershey at Washington University. Dr. Bess Marshall at Washington University kindly shared unpublished data with us, and Mrs. Hongjie Gu performed extensive statistical analyses to calculate the number of patients and duration of the study needed for the trial. Dr. Kent Leslie and Dr. Machelle Manuel at Amylyx have been working with patients to create a patient advisory board for the trial. Ms. Allison Lusis has been assigned to this important project as a lead for the regulatory affairs. My nurse coordinator, Mrs. Stacy Hurst, RN, and lab manager, Mrs. Cris Brown, are ready to conduct this at our medical center. I have been discussing the fundraising strategy for the trial with Mr. Josh Cohen and Mr. Justin Klee, co-CEOs of Amylyx. I have also identified potential grant support from the National Institutes of Health (NIH) and discussed this with a few NIH officers. I will keep on doing my best to start this trial as soon as possible.

Regenerative Gene Therapy 

I am aware that we need a strategy to regenerate damaged tissues in patients with Wolfram syndrome, and my tool to accomplish this goal is to develop regenerative gene therapy. We have been trying to improve visual acuity and brain functions using viral vectors of a healthy Wolfram gene (WFS1) and a regenerative factor called MANF in rodent models of Wolfram and Wolfram iPSC-derived neurons and retinal ganglion cells. Our new preliminary results are encouraging. My goal is to start a trial in the next 3-7 years. It all depends on the fund and results of our pre-clinical studies. 

Base Editing Gene Therapy

The best way to treat genetic disorders is gene-editing or base-editing-based therapy for sure. We have been working with Dr. David Liu’s team (Dr. Gregory Newby) 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 using base editing. This technology uses some components from CRISPR systems together with other enzymes to directly replace the abnormal WFS1 gene with the normal WFS1 gene. We have been getting positive results using iPSCs from Wolfram patients. I hope that we can bring this technology to our patients in the next 3-7 years. 

Wolfram Genetics Clinic

To improve the clinical care for patients with Wolfram syndrome and Wolfram-related disorders, I created a new genetics clinic at the Center for Advanced Medicine, Washington University Medical Center, in 2020. 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. Wolfram syndrome Research Alliance, the Snow Foundation, and the Ellie White Foundation have been referring patients to us (https://wolframsyndrome.wustl.edu/). We accept international patients via our international patient care office. Please call +1-314-273-3780 to make an appointment. US patients can call +1-314-747-7300 to make an appointment.

I have been doing my best to save our patients. I welcome any feedback or questions (urano@wustl.edu). We will work as one team and make a difference together. Thank you for your faith in my work. 

Sincerely,

Fumi Urano, MD, PhD

Samuel E. Schechter Professor of Medicine 

Attending physician at Barnes Jewish Hospital

Washington University School of Medicine

/by
,

Dr Urano’s June 2021 Update

June 2, 2021

 

Dear Friends and Supporters of the Snow Foundation,

Hello everyone. I pray you’re in great spirits. Everyone in my research team has been vaccinated for COVID-19, and we are working very hard to develop novel treatments for Wolfram syndrome. Although our past has been harsh, our future looks brilliant now. I continue adhering to my three guiding principles: 1. Improve clinical care, 2. Raise awareness, and 3. Provide a cutting-edge treatment for Wolfram syndrome. Here are our updates.

An Upcoming Trial

As I repeatedly mentioned in the past, a repurposed drug could be just a band-aid for Wolfram. So, we need a cutting-edge treatment designed explicitly for Wolfram syndrome. We have been focusing our efforts on developing AMX0035 to treat Wolfram syndrome with Amylyx in Cambridge, Massachusetts, in the US. AMX0035 targets endoplasmic reticulum stress (a molecular mechanism of Wolfram) and mitochondria dysfunction. A recent clinical trial of AMX0035 in patients with ALS, an adult-onset neurodegenerative disorder, was successful. Our pre-clinical data using induced pluripotent stem cells (iPSCs)-derived brain cells of Wolfram syndrome and Wolfram mice were positive. These considerations raise the possibility that AMX0035 is a promising medication for patients suffering from Wolfram syndrome. US FDA granted an orphan drug designation of AMX0035 for the treatment of Wolfram syndrome in October 2020. So, we are moving forward to a clinical trial.

Based on what I learned from Dr. Barrett’s clinical trial in Europe, Dr. Hershey’s research clinic in St. Louis, and our dantrolene trial in St. Louis, I designed a new trial protocol for AMX0035 with Dr. Patrick Yeramian and Dr. Jamie Timmons at Amylyx and Dr. Tamara Hershey at Washington University. Dr. Bess Marshall at Washington University kindly shared unpublished data with us, and Mrs. Hongjie Gu performed extensive statistical analyses to calculate the number of patients and duration of the study needed for the trial. Dr. Kent Leslie and Dr. Machelle Manuel have been working with patients to create a patient advisory board for the trial. I have been discussing the fundraising strategy for the trial with Mr. Josh Cohen and Mr. Justin Klee, co-CEOs of Amylyx. Our trial protocol was submitted to the US FDA last week, and I sincerely hope that FDA will allow us to start a trial soon. 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 visual acuity and brain functions using viral vectors of a healthy Wolfram gene (WFS1) and a regenerative factor called MANF in rodent models of Wolfram and Wolfram iPSC-derived neurons and retinal ganglion cells. We are getting encouraging preliminary results. My goal is to start a trial in the next 3-7 years. It all depends on the fund and results of our pre-clinical studies. 

 

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 the abnormal WFS1 gene with the normal WFS1 gene. Our first set of experiments using iPSC from Wolfram patients was a success. We hope that we can bring this technology to our patients in the next 3-7 years. 

Wolfram Genetics Clinic

To improve the clinical care for patients with Wolfram syndrome and Wolfram-related disorders, I created a new genetics clinic at the Center for Advanced Medicine, Washington University Medical Center, in 2020. 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. The Snow Foundation, Wolfram syndrome Research Alliance and the Ellie White 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.

I have been working super hard. I welcome any feedback or questions (urano@wustl.edu). We will work as one team and make a difference together. Thank you for your faith in my work. 

Sincerely,

Fumi Urano, MD, PhD

Samuel E. Schechter Professor of Medicine 

Attending physician at Barnes-Jewish Hospital/Center for Advanced Medicine

Washington University School of Medicine

/by

Dr. Urano’s March 2021 Update

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 

 

/by

Our drug-repurposing Clinical trial of Dantrolene Sodium-Dr. Fumihiko Urano, MD, PhD

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.
/by

New Genetics Clinic for Wolfram syndrome/Wolfram-related disorders-Dr. Fumihiko Urano, MD, Phd

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.

/by

Base Editing Gene Therapy- Dr. Fumihiko Urano, MD, PhD

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.
/by