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
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
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.
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.
WASHINGTON UNIVERSITY’S
2019 WOLFRAM RESEARCH CLINIC UPDATE
Wait no more – the 2019 WU Wolfram Research Clinic planning is underway! We’re sure many of you have lots of questions and hopefully some of them will be answered here. If not, you can always contact Samantha directly. Her contact information is below.
Due to the number of participants enrolled in the clinic and an effort to make the clinic days more manageable, we will be dividing the clinic into two sessions. The official dates for the clinic are as follows:
Group 1 Arrival: Tuesday, 7/9/19
Clinic: Wednesday, 7/10/19 – Friday, 7/12/19
Group 2 Arrival: Sunday, 7/14/19
Clinic: Monday, 7/15/19 – Wednesday, 7/17/19
Scientific Session (TBD) Saturday, 7/13/19
Family Dinner TBD
We are still working out the details of the Scientific Session and the Family Dinner(s) and we will share that information with you as soon as it is finalized. Until then, these are the clinic dates. It is important at this time that you let Samantha know if you have a preference to attend as part of Group 1 or Group 2. Please keep in mind that another person or family cannot communicate your preference for you. Samantha must hear from you directly as to which session you’d like to attend. If you do not have a preference, that works too. You will then be assigned to a group once all preferences are in. The deadline for reserving your slot in a particular group is Jan. 31, 2019. That being said, it is important to get your preference in as soon as possible as we are trying to split the groups evenly which means that your preferred group could reach capacity prior to you stating your preference.
Need Help? For questions or requests regarding the Wolfram Syndrome Research Clinic please contact the WFS Research Clinic Coord., Samantha Ranck, MSW at 314.362.6514 or rancks@npg.wustl.edu
As discussed in a previous newsletter, we have learned
that anxiety and depression symptoms are fairly common
in people with Wolfram Syndrome. These symptoms are
also very common in people without Wolfram Syndrome,
and may be influenced by genes, life stress, and other
factors.
In preliminary examination of our data, I have also noticed
some trends indicating that psychiatric symptoms and
certain types of neurological signs/symptoms might be
related. I plan to further analyze the data to confirm
whether this is true. I would also like to take a closer look
at the brain imaging findings to investigate whether
specific difference in brain structure or function may be
related to specific psychiatric and/or neurological
symptoms.
I also hope to do some investigation comparing the types
of symptoms seen in Wolfram Syndrome to those
reported in other genetic disorders that affect the
functioning of ryanodine receptor calcium channels
(RYRs), which release calcium from the endoplasmic
reticulum (ER) within cells. In Wolfram Syndrome, too
much calcium is released through these channels. Studying
disorders with similar disease mechanisms could help us
understand what produces the symptoms of both
Wolfram Syndrome and other related other disorders. It is
possible that diseases with similar mechanisms may
respond to similar types of treatment.
By Angela M. Reiersen, MD, MPE
Washington University School of Medicine
Dear Wolfram Community:
I am very pleased to announce that we have received
notification from the NIH that our Wolfram natural
history study has been OFFICIALLY FUNDED! This means
that we can start having our Wolfram Research Clinics
again, probably starting next summer and continuing for
5 more years! Samantha, Dr. Marshall and I will begin
planning for the research clinic and will keep you all informed as things move along.
We are excited to continue working with Dr. Bess
Marshall as our caring and dedicated Medical Director!
We will also continue to collaborate with Dr. Fumi Urano
by collecting samples for his lab and coordinating with
the Dantrolene trial. In addition, Dr. Tim Barrett in
Birmingham, UK will share MRIs from his clinical trial, so
that we can learn about individual differences in
neurological progression. Finally, Dr. Gordon Xu, at Mt
Sinai in New York, is helping us measure the optic nerve
with MRI. We are excited to work with all of the
incredible scientists and clinicians on our team.
Thank you for your support and patience during this
time of being in limbo. Please know that we never
stopped caring and we never stopped working on
understanding Wolfram syndrome and its effect on the
brain and its functions. We have high hopes that the
information we gain from this study will have a positive
and lasting impact on all people affected by Wolfram
syndrome! Please call me or Samantha with any questions
about the research clinic.
Sincerely,
Tamara Hershey, PhD
Professor
Scientific Director and Principal Investigator
WU Wolfram Research Clinic
tammy@wustl.edu; 314-362-5593
Our team’s goal is to discover, test and develop treatments in order to prevent or limit visual impairment and to improve the autonomy and the quality of life of patients. Our efforts focus on a very severe form of syndromic Inherited Optic Neuropathy: Wolfram Syndrome (WS). WS is characterized by a rapid degeneration of retinal ganglion cells (RGC) resulting to severe visual impairment before the age of 20 years. To date, there is no treatment to stop the progression of the disease.
The analysis of biological samples from patients with the recessive WS revealed that the WFS1 protein is absent, or less stable, compared to the normal protein. This reduced quantity of WFS1 suggests that the re- expression of WFS1 through gene augmentation therapy could restore the protein function and thus possibly protect the cells from degeneration.
It is important to say that the eye is a perfect model for applying gene therapy approach. It is small, transparent, allowing for very precise visual monitoring. It is also a closed organ, relatively isolated from the rest of the body. RGC are easily accessed by the ocular surgeon who targets them through intravitreal injection, a current routine procedure used to inject medications in various retinal pathologies. In this regard, gene complementation for Wolfram patients is an ideal therapeutic approach to treat visual impairment. Consequently, micro-injection of a vector expressing the human WFS1 cDNA, directly in the vitreous close to the retinal ganglion cell layer should allow to prevent RGC dysfunction and degeneration.
We have studied mice models of WS. Our results indicate that mice reproduced the optic atrophy of WS patients with loss of visual acuity starting at 1 month. We designed a therapeutic vector expressing human WFS1 that we microinjected into the vitreous of Wfs1 mutant mice. We showed that the animals injected with the therapeutic vector have a stabilization of their visual acuity between 3 and 6 months post-injection, a decrease of optic disc pallor and axonal damages. A parallel approach is applied on wild type animals using the same vector in order to assess the innocuousness of the treatment and the transgene expression and distribution. These promising results lead us to continue these therapeutic approach.
Our project consists in demonstrating the validity of the pre-clinical approach to treat Wolfram Syndrome by gene therapy. Obtaining this proof of concept will allow to transfer the protocol to patients assess the therapeutic benefits in the short and medium.
Dr. Cécile Delettre, PhD
cecile.delettre@inserm.fr
http://www.inmfrance.com/inm/en/
Washington University School of Medicine
Clinical Care Update- Bess Marshall, MD
Dear Wolfram families,
As you now have heard from Samantha, I have determined that the Wolfram Research Clinic that was tentatively All of the Wolfram team is sad that we will not be able to see all of you in July. Please know that you are still a very high priority and that this bump will not derail the work at Washington University. We will not allow that to happen! You likely all saw the update from Dr. Barrett in the UK that his intervention trial is not yet underway as they also work through issues, but that it is making progress. Dr. Urano’s dantrolene study is moving along and he will be updating you on those results soon.
The Association du Syndrome de Wolfram meeting is coming up in June and Drs. Hershey and Urano and I will be going to hear updates from the other groups working on the syndrome alongside us, so we will update you in the next newsletter.
Some of the information you all have contributed by participating in the TRACK study was used to develop a paper led by Dr. Barrett’s group: Monogenic diabetes syndromes: Locus-specific databases for Alstrom, Wolfram, and Thiamine-responsive megaloblastic anemia. Human Mutation. 38(7):764-777, 2017 Jul.
This paper analyzes the specific gene changes in 309 people with WFS1 gene alterations in order to determine which changes are likely to cause a particular presentation in a person – for example, some genetic changes cause full-blown Wolfram Syndrome, which others cause diabetes mellitus without other features, others cause hearing loss without other features, etc. This will be very helpful information for patients at the time of diagnosis, getting their genetic testing results and wondering what to expect for their health.
As always, please get in touch if you need assistance with your health or with letters to insurance, etc.
All the best,
Bess Marshall, MD
Pediatric Endocrinologist
Medical Director, WU Wolfram Syndrome Research Clinic
Washington University School of Medicine
Email: Marshall@kids.wustl.edu
Need Help? For questions or requests regarding the Wolfram Syndrome Research Clinic please contact the WFS Research Clinic Coord., Samantha Ranck, MSW at 314.362.6514 or rancks@npg.wustl.edu
Washington University School of Medicine
Wolfram Research Clinic Update- Tamara Hershey, PhD
Dear Research Clinic Families,
As you now have heard from Samantha, I have determined that the Wolfram Research Clinic that was tentatively scheduled for July 2018 will not be able to happen. This was a very difficult decision, but ultimately, we felt it was the most ethical choice. Due to delays in NIH’s funding decision and its impact on our ability to prepare, we just could not provide the kind of experience you deserve and that the research demands. We felt that having a clinic under those circumstances would be a disservice to us all. Please know that we care deeply about you and this research and will start planning with enthusiasm once we get our funding notification. I’m assured by NIH that it will come soon, but there are many bureaucratic hurdles that they have to overcome due to their backlog. While we are very disappointed that the clinic will not happen as we had originally imagined for 2018, we already have several ideas of what we could do to make future clinics even better, such as Tasha’s work on the questionnaires, holding mini clinics throughout the year, and adding some testing of siblings without Wolfram Syndrome. We also continue to work towards analyzing and publishing the data that have already been collected, thus providing other researchers and clinicians with important information. We appreciate your understanding and apologize for the uncertainty that the funding situation has caused. We will keep you informed of any new information. Please feel free to contact me personally with any questions.
Sincerely,
Tamara Hershey, PhD
Professor, Psychiatry & Radiology Departments
Lab Chief, Neuroimaging Labs (NIL) @ MIR
Co-Director, Neuroscience PhD Program, DBBS
Washington University School of Medicine
Email: tammy@wustl.edu
Need Help? For questions or requests regarding the Wolfram Syndrome Research Clinic please contact the WFS Research Clinic Coord., Samantha Ranck, MSW at 314.362.6514 or rancks@npg.wustl.edu
The first update teleconference meeting on Biomarker project led by professor Tim Barrett took place on Tuesday 24 April, six months after the official beginning of the project. Representatives of the three funding organizations were present: Stephanie Gebel (The Snow Foundation), Nolwen Le Floch & Virginie Picard (Association du syndrome de Wolfram) and Lode Carnel (Eye Hope Foundation).
The project coordinator, professor Timothy Barrett, presented the progress of the project, with the kind assistance of two members of his consortium: Drs. Dewi Astuti and Anita Slade (University of Birmingham).
As an introduction, professor Barrett recalled that the project is aimed at validating biomarkers relevant to underlying Wolfram syndrome mechanisms and at developing Patient-Reported Outcomes (PROs) to capture the broader experience of the patient and to define patient-relevant clinical trial endpoints for future clinical trials. The ultimate goal of the project is to hasten delivery of treatments to the patient in the clinic and to develop tools allowing to predict within the first 6 months /1 year of a clinical trial whether a candidate medicine has a chance to succeed or not.
The progress of three workpackages was then presented:
Dr. Anita Slade presented the work she is doing on the development of PROs. She has achieved initial consultations with British patients (adults or adolescents) and parents in order to define what the expected outcomes of a candidate medicine on the patient life and health can be. She has based her research on patients experience as well as on various existing clinical Quality of Life questionnaires that are relevant to Wolfram syndrome and vision loss. She has been able to establish a list of potential PROs that now need to be evaluated for their clinical meaningfulness and usefulness.
Dr. Dewi Astuti next presented her current work on the identification of biomarkers that can be used to evaluate the progress of Wolfram syndrome and more especially the neurodegenerative component of the disease. She has searched for biomarkers that can be preferentially measured in small amounts of blood and that are time and cost-effective. For this, she has made an extensive literature search, looking for candidate biomarkers already used for neurodegenerative diseases. Thanks to this, she has been able to identify 4 new candidate biomarkers that are now being tested for their relevance and sensitivity in cultures of cells depleted of WFS1 gene and in sera of patients with Wolfram syndrome. One of the biomarkers selected seems to be consistently increased in sera of Wolfram patients. Additional assays are ongoing.
Professor Barrett then presented progress being achieved with Euro-WABB, the patient registry for rare diabetes (including Wolfram syndrome). In May 2018, new European standards on data protection will be published, as well as a set of common data elements for all rare disease registries. Moreover, a common consent form for European Reference Networks is now available. The aim of all these new measures is to make all registries interoperable and linked to an EU platform for rare diseases registration. Euro-WABB is currently being modified by Richard Sinnott to comply with these new regulations and requirements. Data from past registry will be transferred to a new, user-friendly database. Hopefully, work will be completed during the summer.
Another project workpackage has not started yet. This workpackage is aimed at validating the first candidate efficacy biomarker p21cip within the frame of the European Phase II clinical trial on candidate drug Valproate. For this, biosamples need to be collected from patients treated and non-treated with the drug. The organization of the clinical trial has faced some delays, but it is now expected to start in Autumn 2018.
This work will be extensively presented at next international workshop organized by the Association du syndrome de Wolfram that will take place in June in Paris, France. The second update teleconference meeting is due in September 2018.
You must be logged in to post a comment.