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.

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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.

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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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GLP-1 receptor agonist liraglutide has a neuroprotective effect on an aged rat model of Wolfram syndrome

Publication: Nature.com | Publication Date: October 31, 2019

Authors: Kadri Seppa, Maarja Toots, Riin Reimets, Toomas Jagomäe, Tuuliki Koppel, Maia Pallase, Stine Hasselholt, Maiken Krogsbæk Mikkelsen, Jens Randel Nyengaard, Eero Vasar, Anton Terasmaa & Mario Plaas

Abstract

Wolfram syndrome (WS) is a rare neurodegenerative disorder that is mainly characterized by diabetes mellitus, optic nerve atrophy, deafness, and progressive brainstem degeneration. Treatment with GLP-1 receptor agonists has shown a promising anti-diabetic effect in WS treatment in both animal models and in human patients. Since previous research has tended to focus on investigation of the WS first symptom, diabetes mellitus, the aim of the present study was to examine liraglutide effect on WS-associated neurodegeneration. We took 9-month-old Wfs1 knock-out (KO) animals that already had developed glucose intolerance and treated them with liraglutide for 6 months. Our research results indicate that 6-month liraglutide treatment reduced neuroinflammation and ameliorated endoplasmic reticulum (ER) stress in the inferior olive of the aged WS rat model. Liraglutide treatment also protected retinal ganglion cells from cell death and optic nerve axons from degeneration. According to this, the results of the present study provide novel insight that GLP-1 receptor agonist liraglutide has a neuroprotective effect in the WS rat model.

Read the entire publication article here.

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Current Landscape of Treatments for Wolfram Syndrome

Publication: ScienceDirect | Publication Date: October 2019

Authors: Damien Abreu, Fumihiko Urano

Wolfram syndrome is a rare genetic spectrum disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration, and ranges from mild to severe clinical symptoms. There is currently no treatment to delay, halt, or reverse the progression of Wolfram syndrome, raising the urgency for innovative therapeutics for this disease. Here, we summarize our vision for developing novel treatment strategies and achieving a cure for Wolfram-syndrome-spectrum disorder.

Read the entire publication article here.

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Dr. Urano’s October 2019 Update

Fumihiko “Fumi” Urano, MDOctober 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

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