The Laboratory of Molecular & Cellular Signaling and its mission in Wolfram Syndrome research

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.

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Summary of activities related to Wolfram syndrome at University of Tartu

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.

 

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Amarantus Bioscience

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.

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Dr. Urano’s June 2019 Update

Fumihiko “Fumi” Urano, MDDear Friends,

The spring has come and the winter has gone. I experienced so many challenging events and incidents during the past winter season, and I feel that we hit the bottom and things have started to move up in the right direction.  Your kind words and encouragement are the engine for my quest to a cure for Wolfram syndrome. It is my pleasure to tell you about our ongoing clinical trial and therapeutic strategies.

A Drug-Repurposing Clinical Trial

Our drug-repurposing clinical trial of dantrolene sodium in patients with Wolfram syndrome is still ongoing. 19 patients could successfully complete the required 6-month phase, and many of them have decided to stay on dantrolene sodium another 18 months. We have determined the appropriate doses for adult and pediatric patients and started seeing encouraging results in their remaining beta cell functions. As this is an open-label study, we cannot conclude that these encouraging results are due to dantrolene sodium. We plan to continue this study until the end of 2019 and move on to the next step.

Because dantrolene sodium was not specifically designed to treat Wolfram syndrome, it may not be optimally suited to address all aspects of Wolfram syndrome pathophysiology. We have been developing novel drugs (endoplasmic reticulum calcium stabilizers) for the treatment of Wolfram syndrome together with a drug development team at the National Institutes of Health. Our new drug candidate seems be safer, more potent and goes to the brain and eyes more efficiently than dantrolene sodium. We are testing this candidate drug in brain cells differentiated from induced pluripotent stem cells (iPSCs) derived from our patients and plan to conduct further studies in humanized Wolfram mice and rats.

Molecular Prosthetics

Another common molecular issue in patients with Wolfram syndrome is cellular stress caused by the expression of mutant Wolfram (WFS1) proteins derived from mutant Wolfram gene (WFS1) variants. To resolve this issue, we have been developing a molecular prosthesis that can optimize the structure of mutant Wolfram protein together with a biotech company in the US. Molecular prosthetics are drugs that can get into the cells and correct the abnormal structure of mutant Wolfram protein in patients’ cells. 

Regenerative Gene Therapy

Our ultimate goal is to provide a cure using regenerative gene therapy. We have been trying to improve visual acuity and brain functions using safe virus expressing healthy Wolfram gene (WFS1) and a regenerative factor called MANF in a rodent model of Wolfram syndrome. In parallel, we are attempting to replace a pathogenic Wolfram gene with a healthy Wolfram gene using a gene editing technology (CRISPR/CAS9).  This work is currently being done using induced pluripotential stem cells (iPSCs) generated for study of treatments for Wolfram syndrome.  

Humanized Wolfram Rats and Mice

To test these cutting-edge therapies, especially gene therapy, we need animal models carrying human Wolfram gene mutations. We have successfully created rats and mice carrying human Wolfram gene mutations. We have started characterizing these animals to assess the efficacy of new treatments. 

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 support. We will decrease human suffering together.


With passion and gratitude,

 

Fumihiko “Fumi” URANO, MD, PhD

Professor of Medicine and Pathology, Samuel E Schechter Endowed Chair
Barnes-Jewish Hospital/Saint Louis Children’s Hospital
Washington University School of Medicine

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RESEARCH UPDATE – Tamara Hershey, PhD

Washington University School of Medicine

Washington-University-Wolfram-Study-group
Washington-University-School-of-Medicine

Dear Wolfram Community,

As we prepare for the research clinic and the community conference with the Snow Foundation, a few other things have been going on that we want you to know about!

First, we have published a paper that describes how the size of brain regions change over time in Wolfram syndrome. This paper is based on the brain imaging that we have done over the last 8 years in the Wolfram research clinic. You can find the paper online here: Evidence for altered neurodevelopment and neurodegeneration in Wolfram syndrome using longitudinal morphometry. The findings have important implications for current and future clinical trials for treating Wolfram syndrome neurodegeneration.

Second, we have continued to interact with other groups that are working on current and future clinical trials, both here in the US, the UK and Belgium.

Finally, we have been working with investigators in Estonia on their mouse model for Wolfram syndrome to determine whether they display similar changes in the brain to people with Wolfram syndrome. If this mouse model is similar in its brain features, we then would be able to do more specific brain studies that might suggest brain-specific treatments.

If you have any questions about any of these research projects, please let me know! I am always happy to talk to you.

Sincerely,

Tamara Hershey, PhD

Professor Scientific Director and Principal Investigator WU Wolfram Research Clinic tammy@wustl.edu

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Try Delicious Wines and Support The Snow Foundation

CellarAngelsDid you know?  All of your wine purchases can now directly support The Snow Foundation.

However, we can’t jet off to wine country any time we want. But, what if The Snow Foundation could bring Napa and Sonoma directly to you? What if we could provide access to private, under-the radar wineries you cannot find anywhere in the market? This is precisely why we partnered with online wine company CellarAngels.com.

Each week Cellar Angels releases a new wine from a small-batch Napa or Sonoma producer located “behind the gates”.  With your every purchase, Cellar Angels donates 10% of the proceeds to The Snow Foundation. Wine lovers, this is such an easy way to show your support for the cause while enjoying access to incredible wines shipped direct to your door. Buy for yourself or send to a loved one, client or colleague as a gift.

How to begin?  Set up your complimentary membership at cellarangels.com and explore the exquisite, rotating selection of wines, watch winemaker interviews and more.  Enter this unique code, charitywelcome0617, at checkout and Cellar Angels will pay ground shipping on your first order.

Welcome to the inner circle of wine wanderlust!

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First Annual Wolfram Syndrome Community Conference

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Wolfram Syndrome-Inheritance Pattern

When Wolfram syndrome is caused by mutations in the WFS1 gene, it is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. Some studies have shown that people who carry one copy of a WFS1 gene mutation are at increased risk of developing individual features of Wolfram syndrome or related features, such as type 2 diabetes, hearing loss, or psychiatric illness. However, other studies have found no increased risk in these individuals.

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Wolfram Syndrome and Hypogonadism

Hypogonadism is seen in some patients. Impaired fertility and erectile dysfunction in male patients and infertility, amenorrhea, and oligomenorrhea in female patients have been reported. These conditions could be treatable and managed in standard way.

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Wolfram Syndrome and Hyponatremia

Most patients with Wolfram syndrome have diabetes mellitus and bladder dysfunction in combination with diabetes insipidus. The dose escalation of desmopressin for the treatment of diabetes insipidus should be carefully done because demopressin may cause hyponatremia. If the sodium in your blood is too low, you have a condition called hyponatremia. You need some sodium in your bloodstream to control how much water is in and around the cells in your body. As a result of low sodium, the amount of water in your body rises and causes your cells to swell. This can lead to many different problems. Some of them are mild. Others can be serious and even life-threatening. Hyponatremia is a common clinical problem in patients with Wolfram syndrome that requires careful management.

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