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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ZOLD Effect of 4-phenylbutyrate and valproate on dominant mutations of WFS1 gene in Wolfram syndrome

Publication: Springer Link | Publication Date: March 26, 2020

Authors: K. Batjargal, T. Tajima, E. F. Jimbo & T. Yamagata

Abstract

Purpose

Wolfram syndrome (WS) is a rare disorder caused by mutations in WFS1 that is characterized by diabetes mellitus, optic atrophy, sensorineural deafness, diabetes insipidus, and neurodegeneration. This disease is usually inherited as an autosomal recessive trait, but an autosomal dominant form has been reported. WFS1 encodes a transmembrane protein, which is a maintenance component of endoplasmic homeostasis. These dominant mutations were thought to increase endoplasmic reticulum (ER) stress. Recent studies suggest that 4-phenylbutyrate (PBA) and valproate (VPA) reduce ER stress. The objective of this study was to analyze the effect of PBA and VPA on dominant WFS1 mutants in vitro.

Read the entire research article here

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Calcium mishandling in absence of primary mitochondrial dysfunction drives cellular pathology in Wolfram Syndrome

Publication: Nature.com | Publication Date: March 16, 2020

Authors: Chiara La Morgia, Alessandra Maresca, Giulia Amore, Laura Ludovica Gramegna, Michele Carbonelli, Emanuela Scimonelli, Alberto Danese, Simone Patergnani, Leonardo Caporali, Francesca Tagliavini, Valentina Del Dotto, Mariantonietta Capristo, Federico Sadun, Piero Barboni, Giacomo Savini, Stefania Evangelisti, Claudio Bianchini, Maria Lucia Valentino, Rocco Liguori, Caterina Tonon, Carlotta Giorgi, Paolo Pinton, Raffaele Lodi & Valerio Carelli

Abstract

Wolfram syndrome (WS) is a recessive multisystem disorder defined by the association of diabetes mellitus and optic atrophy, reminiscent of mitochondrial diseases. The role played by mitochondria remains elusive, with contradictory results on the occurrence of mitochondrial dysfunction. Read more

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Taste and smell function in Wolfram syndrome

Publication: Orphanet Journal of Rare Diseases | Publication Date: February 22, 2020

Authors: Raul Alfaro, Tasha Doty, Anagha Narayanan, Heather Lugar, Tamara Hershey & M. Yanina Pepino

Abstract

Background: Wolfram syndrome is a rare genetic disease characterized by insulin-dependent diabetes, optic nerve atrophy, sensorineural hearing loss and neurodegeneration. Read more

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ZOLD Wolfram syndrome 1 gene regulates pathways maintaining beta-cell health and survival

Publication: Nature.com | Publication Date: February 14, 2020

Authors: Damien Abreu, Rie Asada, John M. P. Revilla, Zeno Lavagnino, Kelly Kries, David W. Piston & Fumihiko Urano

Abstract

Wolfram Syndrome 1 (WFS1) protein is an endoplasmic reticulum (ER) factor whose deficiency results in juvenile-onset diabetes secondary to cellular dysfunction and apoptosis. The mechanisms guiding β-cell outcomes secondary to WFS1 function, however, remain unclear. Here, we show that WFS1 preserves normal β-cell physiology by promoting insulin biosynthesis and negatively regulating ER stress. Depletion of Wfs1 in vivo and in vitro causes functional defects in glucose-stimulated insulin secretion and insulin content, triggering Chop-mediated apoptotic pathways. Genetic proof of concept studies coupled with RNA-seq reveal that increasing WFS1 confers a functional and a survival advantage to β-cells under ER stress by increasing insulin gene expression and downregulating the Chop-Trib3 axis, thereby activating Akt pathways. Remarkably, WFS1 and INS levels are reduced in type-2 diabetic (T2DM) islets, suggesting that WFS1 may contribute to T2DM β-cell pathology. Taken together, this work reveals essential pathways regulated by WFS1 to control β-cell survival and function primarily through preservation of ER homeostasis.

Read the entire research article here

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Dr. Urano’s January 2020 Update

Fumihiko “Fumi” Urano, MDJanuary 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

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High Prevalence of a Monogenic Cause in Han Chinese Diagnosed With Type 1 Diabetes, Partly Driven by Nonsyndromic Recessive WFS1 Mutations

Publication: American Diabetes Association | Publication Date: January 2020

Authors: Meihang Li, Sihua Wang, Kuanfeng Xu, Yang Chen, Qi Fu, Yong Gu, Yun Shi, Mei Zhang, Min Sun, Heng Chen, Xiuqun Han, Yangxi Li, Zhoukai Tang, Lejing Cai, Zhiqiang Li, Yongyong Shi, Tao Yang and Constantin Polychronakos

Abstract

It is estimated that ∼1% of European ancestry patients clinically diagnosed with type 1 diabetes (T1D) actually have monogenic forms of the disease. Because of the much lower incidence of true T1D in East Asians, we hypothesized that the percentage would be much higher. Read more

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Clinical and genetic analysis of two wolfram syndrome families with high occurrence of wolfram syndrome and diabetes type II: a case report

Publication: BMC Medical Genetics | Publication Date: January 14, 2020

Authors: Maryam Sobhani, Mohammad Amin Tabatabaiefar, Soudeh Ghafouri-Fard, Asadollah Rajab, Asal Hojjat, Abdol-Mohammad Kajbafzadeh & Mohammad Reza Noori-Daloii

Abstract

Conclusions: The mutational and phenotypic spectrum of WS is broadened by our report of novel WFS1 mutation. Our results reveal the value of molecular analysis of WFS1 in the improvement of clinical diagnostics for WS. Read more

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