Dr. Urano’s September 2020 Update

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:
therapeutic-development-pipelines-and-timeline

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.
Fumihiko “Fumi” Urano, MD
Sincerely,

Fumi Urano, MD, PhD

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Update on TreatWolfram Clinical Trial

September 2020

Dear friends and colleagues, to recap, this is a trial of sodium valproate given by mouth, for 3 years, to try and slow down the progress of vision loss in Wolfram. It involves 4 countries in Europe, and is comparing the effects of sodium valproate to placebo. The trial recruited its first patient in January 2019. We currently have 12 recruits at our children’s hospital site in Birmingham, looked after by my colleague Dr Renuka Dias. We had a pause due to Coronavirus, but I am very pleased to say that Dr Ben Wright has just recruited our first adult patient at the adult site in Birmingham. With lots of help from our international colleagues, we now have all the regulatory approvals in place in each country. We spoke with Dr Gema Esteban in Spain this week, and she will recruit her first patient in October. We hope to complete recruitment in June 2021.

We now have really accurate and reproducible assessments in each site so that we can pool the results. Our independent data monitoring committee sees all the unmasked results and if there is a strong signal of effect, or signal of no effect, they will let us know without waiting for the end of the trial.

I am very grateful to everyone who is taking part or about to take part in this trial; and we are learning a lot about how to deliver clinical trials in Wolfram, for the future. Wolfram syndrome UK have been brilliant in supporting families to attend study visits; and we are very grateful to The Snow Foundation, Eye Hope Foundation, and Association Syndrome de Wolfram for support to collect research samples, which will be available to the whole Wolfram syndrome community.

Sincerely

Dr Timothy Barrett

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Amarantus Bioscience: MANF

MANF (mesencephalic-astrocyte-derived neurotrophic factor) is believed to have broad potential because it is a naturally-occurring protein produced by the body for the purpose of reducing and preventing apoptosis (cell death) in response to injury or disease, via the unfolded protein response. By manufacturing MANF and administering it to the body, Amarantus is seeking to use a regenerative medicine approach to assist the body with higher quantities of MANF when needed. Amarantus is the front-runner and primary holder of intellectual property (IP) around MANF, and is initially focusing on the development of MANF-based protein therapeutics.

Learn more

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ZOLD Calpain inhibitor and ibudilast rescue β cell functions in a cellular model of Wolfram syndrome

Publication: PNAS.org | Publication Date: July 21, 2020

Authors: Lien D. Nguyen, Tom T. Fischer, Damien Abreu, Alfredo Arroyo, Fumihiko Urano, and Barbara E. Ehrlich

Significance

Wolfram syndrome is a rare multisystem disease characterized by diabetes insipidus, diabetes mellitus, optic nerve atrophy, and deafness (DIDMOAD). It is primarily caused by mutations in the Wolfram syndrome 1 gene, WFS1. As a monogenetic disorder, Wolfram syndrome is a model for diabetes and neurodegeneration. There is no effective treatment for this invariably fatal disease. Here we characterize WFS1 as a regulator of calcium homeostasis and subsequently target calcium signaling to reverse deficits in a cellular model of Wolfram syndrome.

Read the entire research article here

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Characterization of an induced pluripotent stem cell line (IMBPASi001-A) derived from fibroblasts of a patient affected by Wolfram Syndrome

Publication: ScienceDirect.com | Publication Date: July 2020

Authors: Dawid P.Grzela, Beata Marciniak, Lukasz Pulaski

Abstract

Wolfram Syndrome is a rare, autosomal recessive genetic disorder with clinical symptoms appearing in early childhood. Here, we report a generation of iPSCs from fibroblasts of a patient affected by this disease. Read more

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Trial of Liraglutide in Wolfram Syndrome

Washington-University-School-of-MedicineDear Families:

We (Drs. White, Marshall, Urano, and Hershey) are excited to announce that we are now funded to perform a clinical trial of liraglutide (Victoza®; NovoNordisk) in Wolfram Syndrome.  Led by Drs. White and Marshall, this study will focus on the tolerability and safety of liraglutide and possible beneficial effects. We are inviting all participants over 10 years old in the Wolfram Research Clinic to participate in this study.  

Liraglutide is a compound that is a glucagon-like peptide-1 (GLP-1) receptor agonist; that is, it acts like the natural hormone GLP-1.  GLP-1 increases the release of insulin from the pancreas after a meal and slows down the digestion of the meal; this lowers blood sugars in people with type 2 diabetes.  Liraglutide is approved by the Food and Drug Administration (FDA) for use in adults and children older than 10 years old with type 2 diabetes.  In animal models of Wolfram syndrome, liraglutide has also been shown to slow the progression of diabetes, and possibly neurodegeneration.  It is not known if this is also true in people with Wolfram Syndrome.

Participation in this study would require injecting liraglutide once a day for 12 months.  Being on liraglutide will likely lower blood sugars and insulin doses, but it is unlikely to eliminate the need for insulin completely. In addition, evaluations of insulin secretion, vision, and an MRI would be conducted at the annual research clinic, and data would be shared between those two studies.  Participation in this study is voluntary, and you will be free not to participate or to stop participating at any time, and you will still be able to keep participating in the research clinic.

If you are interested in learning more about this study we will discuss it with you during your visit to the Wolfram Syndrome Research Clinic, or you can contact Dr. Neil White at (314) 286-1157 or Dr. Bess Marshall at (314) 454-6051, and we can discuss it with you further.  

Neil H. White, MD (314) 286-1157

Bess A. Marshall, MD (314) 454-6051

Fumihiko Urano, MD, Ph.D.

Tamara Hershey, PhD

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A soluble endoplasmic reticulum factor as regenerative therapy for Wolfram syndrome

Publication: Nature.com | Publication Date: May 4, 2020

Authors: Jana Mahadevan, Shuntaro Morikawa, Takuya Yagi, Damien Abreu, Simin Lu, Kohsuke Kanekura, Cris M. Brown & Fumihiko Urano

Abstract

Endoplasmic reticulum (ER) stress-mediated cell death is an emerging target for human chronic disorders, including neurodegeneration and diabetes. However, there is currently no treatment for preventing ER stress-mediated cell death. Here, we show that mesencephalic astrocyte-derived neurotrophic factor (MANF), a neurotrophic factor secreted from ER stressed cells, prevents ER stress-mediated β cell death and enhances β cell proliferation in cell and mouse models of Wolfram syndrome, a prototype of ER disorders. Read more

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Dr. Urano’s April 2020 Update

Fumihiko “Fumi” Urano, MD

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

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ZOLD Gene-edited human stem cell–derived β cells from a patient with monogenic diabetes reverse preexisting diabetes in mice

Publication: Science Translational Medicine | Publication Date: April 22, 2020

Authors: Kristina G. Maxwell, Punn Augsornworawat, Leonardo Velazco-Cruz, Michelle H. Kim, Rie Asada, Nathaniel J. Hogrebe, Shuntaro Morikawa, Fumihiko Urano, Jeffrey R. Millman

Repaired β cells for replacement therapy

Wolfram syndrome is a recessive genetic disease caused by mutations in WFS1 (Wolfram syndrome 1) and can present with a multitude of symptoms including diabetes, optic atrophy, and neurological problems. There is currently no cure and patients are managed with symptomatic treatment. Maxwell et al. corrected a WFS1 pathogenic variant in patient fibroblast-derived induced pluripotent stem cells (iPSCs) that they then differentiated to pancreatic β cells. The gene-corrected β cells showed improved glucose-stimulated insulin secretion and reversed hyperglycemia for 6 months after their transplantation into diabetic mice. This study may open up the possibility of autologous β cell transplants for patients with Wolfram syndrome.

Read the entire research article here

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ZOLD Neuronal Calcium Sensor 1 (NCS1) as a Potential Drug Target for Treatment of Wolfram Syndrome

Publication: The Faseb Journal | Publication Date: April 15, 2020

Authors: Tom T. Fischer, Lien D. Nguyen, Barbara E. Ehrlich

Abstract

Wolfram syndrome (WS) is an orphan, autosomal recessive neuroendocrinological disease that affects approximately 1 in 500,000 people worldwide. Patients develop diabetes mellitus, diabetes insipidus, optical atrophy, and hearing loss and usually die in their 30s. The majority of cases are attributed to mutations in a single gene, WFS1, which encodes for the protein wolframin. Despite the known genetic cause, there is currently no direct treatment for WS. This lack of therapy is because the regular functions of wolframin, and the pathophysiological consequences following the loss of intact WFS1, remain elusive. Here, we further examined the function of WFS1 in the context of glucose toxicity, to address the earliest diagnosed symptom of WS which is the onset of diabetes mellitus near age 6. Based on a recent study, we aimed to show that WFS1 interaction with a calcium binding protein, neuronal calcium sensor 1 (NCS1), is important for its normal functions. NCS1 is known to regulate exocytosis, promote cell survival, and maintain calcium homeostasis. We showed that knocking out WFS1 in rat insulinoma (INS1) cells resulted in increased baseline calcium, reduced ATP‐evoked inositol‐trisphosphate receptor (InsP3R)‐dependent calcium response, reduced phospho‐Akt (Ser473), and increased vulnerability to high glucose treatment. Furthermore, both INS1 control (CTRL) and WFS1 knockout (KO) cells showed increased NCS1 mRNA following high glucose treatment. However, only the CTRL cells showed increased NCS1 protein expression, whereas WFS1 KO cells showed decreased NCS1 expression. These results suggest that NCS1‐WFS1 interaction protects NCS1 from degradation, potentially by the calcium‐dependent protease calpain. Lastly, we showed that overexpression of NCS1, or treatment with a putative NCS1‐binding drug, rescued the deficits observed in WFS1 KO cells. Overall, we demonstrated a physiological function of the WFS1‐NCS1 interaction and that protecting NCS1 levels can ameliorate the deficits caused by loss of WFS1. These findings will facilitate the discovery of drugs that can prevent or reduce the symptoms of WS.

Read the entire research article here

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