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

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

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

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

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.

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.

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

The Laboratory of Molecular & Cellular Signaling (LMCS; https://gbiomed.kuleuven.be/english/research/50000618/50753344), co-directed by Prof. Jan B. Parys & Prof. Geert Bultynck, is part of the Department of Cellular and Molecular Medicine at KU Leuven. The research team studies intracellular Ca2+ signals and Ca2+-controlled processes such as cell death and cellular bio-energetics in human cells. Furthermore, the team aspires to elucidate how these Ca2+ signals contribute to human health and to disease when such signals are disturbed. Hence, by targeting the function of intracellular Ca2+-transport system, we hope to develop novel strategies to tackle such disease states or reduce disease burden. The lab has focused on diseases associated with suppressed Ca2+ signaling, such as cancer, as well as with excessive Ca2+ signaling, such as acute pancreatitis. For its research activities, the lab collaborates with several teams at KU Leuven, in Belgium and around the globe. To foster research collaboration among its partners and to serve as a Ca2+-signaling hub for other researchers, the lab has established a research community “Ca2+ signaling in health, disease & therapy” supported by the Research Foundation – Flanders (CaSign; www.casign.org).

Very recently and thanks to a recently established research alliance with Dr. Kaasik (Tartu University, Estonia) supported by CELSA (Central Europe Leuven Strategic Alliance), LMCS has included Wolfram Syndrome within its strategic ambitions for future research programs. The team aims to develop novel strategies to tackle Wolfram syndrome by targeting the Ca2+-signaling machinery and restoring Ca2+ homeostasis in cells. In cell systems that serve as a model for Wolfram Syndrome, the team will explore the role of anti-apoptotic Bcl-2 proteins in Ca2+-signaling dysregulation, since these proteins are key modulators of intracellular Ca2+-release channels perturbed in Wolfram Syndrome Type 1 and Type 2. Next, the team will exploit recently obtained insights in the interplay between Bcl-2-protein function and Ca2+ signaling to develop novel strategies to fight Ca2+-driven disease outcomes in Wolfram syndrome. In the (long-term) future with the help of several local partners at KU Leuven & its international network of collaborators (to whom we are very grateful), LMCS strives to translate their findings towards patient-derived cell models, such as fibroblasts and neuronal, eye, brain cell types differentiated from stem cells and to develop strategies to apply such tools in the eye or the brain. The team hopes to develop these research endeavors with the critical support from national funding agencies but also from foundations such as Eye Hope and SNOW Foundation.

Who is who in Wolfram research @ LMCS, KU Leuven

Geert Bultynck is a Professor & Principle Investigator at the Laboratory of Molecular & Cellular Signaling, Department of Cellular & Molecular Medicine, KU Leuven. His research focuses on exploring & exploiting intra- and intercellular Ca2+ signaling in health, disease & therapy. He teaches Cell Physiology and Human Physiology. He will direct & supervise the research on Wolfram syndrome. When Geert is not doing research/teaching, you can find him on the badminton pitch, the stands of his favorite soccer team, at the hobbies of his 2 children or travelling with his wife & children.

Tim Vervliet is a postdoctoral researcher at the Laboratory of Molecular & Cellular Signaling. Tim is supported by a fellowship from the Research Foundation – Flanders (FWO). His research focuses on the role of ryanodine receptor Ca2+ channels in cell function & disease, including neurodegenerative diseases. He teaches a work session on Ion Channels. He will perform research on Wolfram syndrome, but also supervise and train new students arriving in the lab. When Tim is not doing research, he is renovating his house, taking care of the vegetable garden or going out with his friends.

Rita La Rovere is a part-time technical expert at the Laboratory of Molecular & Cellular Signaling and helps out several PhD students & postdocs with their projects. Rita will provide technical support to the research on Wolfram syndrome. When Rita is not in the lab, you can find her most of the time at home, focusing on her daughters’ activities and the family needs. She also likes Italian cooking and spends time outside with her family.

Jens Loncke currently is a last year student in the Master of Biochemistry & Biotechnology. Jens will join the Laboratory of Molecular & Cellular Signaling in September 2019 for a 4-years PhD project aiming to study Ca2+ signaling and Bcl-2-protein function in Wolfram syndrome. We are grateful and excited that the Eye Hope Foundation recently decided to support Jens’ PhD project (1 year PhD salary). Further support for Jens and his project is sought from external sources, including the SNOW Foundation. When Jens is not studying/doing research, he enjoys listening to music at concerts or playing music himself. As an outdoors person, he enjoys hiking and practicing sports in open air.

Marth Briers currently is 3rd year Bachelor student in the Master of Pharmaceutical Sciences. Marth will join the Laboratory of Molecular & Cellular Signaling during the summer of 2019. To support her stay in the lab, she applied for a student internship grant from the Biochemical Society – UK. Marth will work on the biochemical link between CISD2 and Bcl-2 in Ca2+-signaling control. When Mart is not studying, you can find her on the tennis court, on the playground as a scouts guide or enjoying a drink with friends.

By Mario Plaas and Anton Terasmaa

Wfs1 KO rats. These rats were used for 5 months long Liraglutide experiment.

At University of Tartu we have created and characterized Wfs1 knock-out (Wfs1 KO) rat, which exhibits symptoms of Wolfram syndrome (WS), including diabetes mellitus, optic atrophy and degeneration of brainstem [1]. Thus, rat model mimics human condition, is well suited to study molecular mechanism of WS and to evaluate pharmacological treatment strategies. Our activities are mostly related to evaluation of pharmacological treatments in rat model of WS. While performing this work we also try to understand the molecular pathology of WS using histological and molecular biology methods.

We have evaluated effect of GLP1 receptor agonist Liraglutide in the rat model of WS. One week treatment with GLP1 receptor agonist markedly improved diabetic phenotype of these rats. We therefore have tested the effect of 5 months long treatment with GLP1 RA Liraglutide in Wfs1 KO rat, this treatment resulted in an improvement of diabetic phenotype, reduction of ER stress levels and preservation of remaining beta cell mass [2]. Our next study was aimed at evaluation of neuroprotective effects of Liraglutide in the rat model of WS. For this purpose older Wfs1 KO rats were treated with liraglutide for 6 months. Thereafter, number on neurons was evaluated in the brainstem and retina of these rats using stereology. We expect to publish the results of this study very soon. 

In parallel, using similar tactics as with Liraglutide, we are evaluating also alternative pharmacological treatment options in our rat model of WS. For this purpose we treat animals with promising drug candidates and evaluate their effects on progression of symptoms of WS. This approach could be the fastest way to find and introduce new treatment options.

 

1. Plaas, M., et al., Wfs1- deficient rats develop primary symptoms of Wolfram syndrome: insulin-dependent diabetes, optic nerve atrophy and medullary degeneration. Sci Rep, 2017. 7(1): p. 10220.

2. Toots, M., et al., Preventive treatment with liraglutide protects against development of glucose intolerance in a rat model of Wolfram syndrome. Sci Rep, 2018. 8(1): p. 10183.

 

MANF Therapeutics is developing mesencephalic astrocyte-derived neurotrophic factor (MANF) as a therapeutic protein for the treatment of certain protein-misfolding and neurological disorders. MANF is currently in pre-clinical development as a disease modifying treatment for Parkinson’s disease and Wolfram’s Syndrome. In Wolfram’s, many of the key disease etiologies, including vision loss, hearing loss, diabetes and neurodegeneration have protein misfolding as a key molecular signature that MANF could potentially address. The lead application for MANF in Wolfram’s is for the treatment of vision loss. MANF has demonstrated safety and efficacy in animals for the treatment of retinal degeneration, including the increased protection and function of rods, cones and retinal ganglion cells in the retina. Leading scientists in the Wolfram’s community believe MANF could be the first disease-modifying treatment developed for the disease. MANF Therapeutics is in the process of raising capital to support preparations for clinical trials, and thereafter the initiation of human clinical trials in Wolfram’s Syndrome and Parkinson’s. Once the capital is raised, it will take approximately 12-18 months to start clinical development.