Authors: N. B. Toppings, J. M. McMillan, P. Y. B. Au, O. Suchowersky and L. E. Donovan
Abstract
Background. Classical Wolfram syndrome (WS) is a rare autosomal recessive disorder caused by mutations in WFS1, a gene implicated in endoplasmic reticulum (ER) and mitochondrial function. WS is characterized by insulin-requiring diabetes mellitus and optic atrophy. A constellation of other features contributes to the acronym DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness). This review seeks to raise awareness of this rare form of diabetes so that individuals with WS are identified and provided with appropriate care. Case. We describe a woman without risk factors for gestational or type 2 diabetes who presented with gestational diabetes (GDM) at the age of 39 years during her first and only pregnancy. Although she had optic atrophy since the age of 10 years, WS was not considered as her diagnosis until she presented with GDM. Biallelic mutations in WFS1 were identified, supporting a diagnosis of classical WS. Conclusions. The distinct natural history, complications, and differences in management reinforce the importance of distinguishing WS from other forms of diabetes. Recent advances in the genetics and pathophysiology of WS have led to promising new therapeutic considerations that may preserve β-cell function and slow progressive neurological decline. Insight into the pathophysiology of WS may also inform strategies for β-cell preservation for individuals with type 1 and 2 diabetes.
http://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svg00The Snow Foundationhttp://thesnowfoundation.org/wp-content/uploads/2019/06/snow-foundation_logo.svgThe Snow Foundation2018-08-27 06:44:482020-09-07 13:11:23Wolfram Syndrome: A Case Report and Review of Clinical Manifestations, Genetics Pathophysiology, and Potential Therapies
I’d like to begin by thanking all of you for your continued support, trust, and faith in me. I always feel your support and energy. It is always my pleasure to update you about our progress.
To achieve a cure for Wolfram syndrome, we need breakthrough treatments. We currently have three new candidate drugs that can potentially delay or halt the progression of Wolfram syndrome. In parallel, we are developing regenerative gene therapy to protect and regrow remaining eye and brain cells. We usually test the efficacy of candidate drugs and gene therapies in cell models of Wolfram syndrome first. Wolfram cell models are cells derived from our patients or cells lacking normal Wolfram syndrome 1 gene. These cells are sensitive to cell stress and susceptible to cell death. So we are looking for candidate drugs and gene therapies that can reduce cell stress and cell death in Wolfram cell models. The advantage of using cell models is that we can test multiple drug candidates at the same time within a few months. As a next step, we use a mouse model of Wolfram syndrome to test the efficacy of new treatments on visual acuity, brain function, and diabetes. These are genetically engineered mice that do not have Wolfram syndrome 1 gene and develop diabetes, visual impairment, and brain dysfunction. Although these mice are quite useful, it is challenging to test the efficacy of a type of gene therapy called gene editing because they don’t carry abnormal Wolfram syndrome 1 gene variants that our patients carry. In addition, because mice are so small, it is challenging for us to test the efficacy of new treatments in their eyes. Their eyes are so small. To overcome these challenges, I have designed mice and rats carrying Wolfram syndrome 1 gene variants that our patients carry. We call them humanized Wolfram mice and rats. If successful, we can test our new gene therapy and assess the efficacy of new treatments on visual acuity in these humanized Wolfram mice and rats. This will accelerate the pace of our therapeutic development.
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. I cannot thank you enough.
It is nice to see you again. I always appreciate your support, trust, and faith in me. I see patients with Wolfram syndrome every week and receive phone calls and emails from patients and their families every single day. It is definitely urgent to slow the progression of the disease and develop novel treatments for achieving a cure.
I attended two important meetings in the past two weeks. From June 11th to June 12th, I attended the International Wolfram Syndrome Workshop in Paris, France, hosted by the French Wolfram Syndrome Association. I attended the first workshop in 2009 together with just 11 other researchers from all over the world. I was the only researcher from the US then. At the first workshop, we agreed to create patient registries and research & service clinics for future clinical trials. As of today, these goals have been achieved, and two drug-repurposing clinical trials are ongoing (https://wolframsyndrome.dom.wustl.edu/clinical-trials/). I met with late Dr. Alan Permutt from Washington University and Mrs. Stephanie Snow Gebel who founded the Snow Foundation at the workshop in 2010, which made me decide to move to Washington University in 2012. At this year’s workshop, almost 50 researchers attended and presented their progress. I presented our progress on our clinical trial and gene therapy strategies.My colleague, Dr. Tammy Hershey, presented MRI findings in patients with Wolfram syndrome. My long-term collaborator, Dr. Tim Barrett in the UK, presented his progress on their clinical trial. I met with multiple collaborators and saw representatives of patient organizations from US, UK, Italy, Spain, Belgium, and France. I was glad to see that the International Wolfram research group had grown. I was glad that all the researchers had been collaborative. I was grateful for everything patient organizations had done for our patients and families, doctors, and researchers.
On Monday, June 25th, I presented my concept of Wolfram spectrum disorder at the American Diabetes Associationmeeting in Orlando, Florida. I believe there are at least three different types of clinical manifestations in Wolfram syndrome and Wolfram-like disorder: mild, intermediate, and severe. I have been developing genetic testing to further understand the spectrum of Wolfram syndrome. Some of our new treatments could be beneficial for patients with all three types in theory. We also need to develop specific treatments for each type.
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. Good things happen to people who do good things.
“I believe that Wolfram syndrome is an underdiagnosed disease. Wolfram syndrome is characterized by juvenile-onset diabetes, optic nerve atrophy, diabetes insipidus, deafness, neurogenic bladder, and symptoms related to brain cell dysfunction. However, I have discovered that Wolfram syndrome gene (WFS1) mutations result in manifestations that range from mild to severe. I know diabetes patients who carry WFS1 gene mutations and have not developed any other cardinal symptoms of Wolfram syndrome, such as optic nerve atrophy. This is called the spectrum of disease. To provide an accurate diagnosis, I have been developing “genetic testing” for screening Wolfram syndrome and Wolfram-related diseases. Using a single tube of blood, I would like to provide an accurate diagnosis. An accurate diagnosis serves as a basis for targeted therapy. An accurate diagnosis provides a sense of relief”.
As always, please feel free to contact me with any questions or concerns.
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
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
1st teleconference meeting report
Tuesday 24 April, 2018
Report written by: Virginie Picard (Association du syndrome de Wolfram) Report validated by: prof. Timothy Barrett, project coordinator
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.
Mitochon Pharmaceuticals, Inc., Blue Bell, Pennsylvania, is sponsoring a Proof of Concept (POC) study in Wolfram mice using a mitochondrial target approach to attenuate diabetes, behavioral and functional decline. Mitochon has developed clinical stage (Phase I ready) pharmaceuticals that modulate mitochondrial physiology.These compounds, MP101 and MP201, have shown merit in animal models of vision loss, hearing loss, movement disorders, trauma, neuromuscular/neurodegenerative and metabolic diseases. Stephanie Gebel recommended Dr. Sulev Koks at the University of Tartu, Estonia, who generated the Wsf1 KO mice to the company.Dr. Geisler, CSO of Mitochon, said, “I was delighted to hear Dr. Koks outside the box spirit for embracing new ideas and for seeing the possible merits of our approach for Wolfram”.Dr. Saad Naseer provided Mitochon some guidance to capture critical endpoints as well.
The concept is that endoplasmic reticulum (ER) stress associated with Wolfram Syndrome has a strong detrimental effect on the mitochondria and thus cellular survival. In addition, the abundance of oxidative stress in Wolfram through reactive oxygen species (ROS) production via the mitochondria further creates a hostile environment for cells.Unlike anti-oxidants that attempt to mop up ROSs once they are made, Mitochon’s compounds, MP101/MP201, abolish overt ROS production in the mitochondria, which is a much better starting point, and reduce the burden of mitochondrial calcium overload due to ER stress.Together, these targeted approaches have been shown to prevent cell death. Dr. Geisler says “There are many diseases, such as Alzheimer’s, Parkinson, Huntington, epilepsy, Wolfram, Multiple Sclerosis, etc., that have both ER and oxidative stress issues. Our therapies work by helping the mitochondria to cope with the deleterious effects of ER stress.”
With ER stress, the mitochondria get overburdened with calcium coming from the endoplasmic reticulum.One of the main roles of the mitochondria, besides making energy (ATP), is to store calcium and to keep the cytosol calcium free. The calcium storage capacity of the mitochondria is tremendous, but there is a threshold.When that threshold is exceeded, the mitochondria will self-destruct and leak out all of the calcium into the cytoplasm. The neighboring mitochondria are obligated to take it up, but are already near their threshold, so they self-destruct. Eventually, this cascades into the death of cells such as neurons or myotubes (muscle cell).Reducing ER stress is a great approach, but lowering calcium overload at the mitochondria is critical.Since Mitochon’s compounds (MP101 and MP201) simultaneously abolish ROS production and reduce calcium overload, their targeted effects should lower the burden on mitochondria and preserve cellular health in diseases that exhibit these types of stressors. This has already been shown in models of Huntington’s disease, traumatic brain injury (TBI), and Duchenne Muscular Dystrophy DMD) and the plan is to provide evidence that this approach is useful in Wolfram Syndrome.
Dr. Geisler says, “in a nutshell, we plan to run both compounds (MP101 and MP201) in the Wfs1KO mouse starting at 2-mths of age when diabetes starts to appear. They will be orally dosed once per day for 4-mths until 6-mths of age. An oral glucose tolerance test (OGTT) will be performed each month to monitor changes in glucose flux. At the end of the study, behavior will be monitored for balance and gait. Finally, the pancreas will be removed to examine islet morphology (diameter and number), the liver will be used to measure steatosis, histology on the eyes for retinal ganglion cell (RGC) survival and the optic nerve for demyelination.We expect the study to start in July 2018 and complete in early 2019.We don’t know for sure if it will work, but it seems reasonable! We already have data on preventing hearing loss, vision loss, diabetes, neuroprotection, neuromuscular protection, and calcium overload, so Wolfram looks like a plausible target.”
About Mitochon Pharmaceuticals
Mitochon was founded in 2014 by experienced Pharma executives with the mission to develop treatments for insidious diseases through the modulation of mitochondrial physiology, with applications to neurodegeneration (Huntington’s, Parkinson’s, MS) neuromuscular (Duchenne) and developmental (Wolfram Syndrome) diseases. Mitochon’s lead programs, MP101 and MP201, specifically harnesses the power of the mitochondria to provide broad neural protection. These compounds elicit mild increases in energy expenditure that result in strengthening cellular survival – similar to the positive effects seen with fasting and exercise. These compounds also induce an important neurotrophin, Brain Derived Neurotrophic Factor (BDNF), involved in cognition and neural growth. Mitochon is supported by Ben Franklin Technology Partners Southeastern PA, an initiative of the Pennsylvania Department of Community and Economic Development funded by the Ben Franklin Technology Development Authority. Additional Information: www.mitochonpharma.com
For background information, please see [1-5]
Feissner, R.F., et al., Crosstalk signaling between mitochondrial Ca2+ and ROS. Front Biosci (Landmark Ed), 2009. 14: p. 1197-218.
Geisler, J.G., et al., DNP, mitochondrial uncoupling, and neuroprotection: A little dab’ll do ya. Alzheimers Dement, 2017. 13(5): p. 582-591.
Geisler, J.G., Targeting energy expenditure via fuel switching and beyond. Diabetologia, 2011. 54(2): p. 237-44.
Wu, B., et al., 2,4 DNP Improves Motor Function, Preserves Medium Spiny Neuronal Identity, and Reduces Oxidative Stress in a Mouse Model of Huntington’s disease. Experimental Neurology, 2017. 293(Mar 28): p. 83-90.
Khan, R.S., et al., Mitochondrial Uncoupler Prodrug of 2,4-Dinitrophenol, MP201, Prevents Neuronal Damage and Preserves Vision in Experimental Optic Neuritis. Oxid Med Cell Longev, 2017. 2017: p. 7180632.
August 9
Mitochon Pharmaceuticals, Inc., Blue Bell, Pennsylvania, is sponsoring a Proof of Concept (POC) study in Wolfram mice using a mitochondrial target approach to attenuate diabetes, behavioral and functional decline. Mitochon has developed clinical stage (Phase I ready) pharmaceuticals that modulate mitochondrial physiology.
You must be logged in to post a comment.