1^st 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 p21^cip 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]

1. Feissner, R.F., et al., Crosstalk signaling between mitochondrial Ca2+ and ROS. Front Biosci (Landmark Ed), 2009. 14: p. 1197-218.
2. Geisler, J.G., et al., DNP, mitochondrial uncoupling, and neuroprotection: A little dab’ll do ya. Alzheimers Dement, 2017. 13(5): p. 582-591.
3. Geisler, J.G., Targeting energy expenditure via fuel switching and beyond. Diabetologia, 2011. 54(2): p. 237-44.
4. 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.
5. 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.

  Washington University School of Medicine

Wolfram Research Clinic Update- Tamara Hershey, PhD

The main activity in our lab right now is the furious planning process for the 2018 Wolfram Research Clinic! However, we also have some other progress to report. First, in the past month, we have submitted two new papers on Wolfram Syndrome for review, both based on data from previous research clinics. One of the papers is on the very important topic of urological symptoms. The paper reports on the common urological issues in Wolfram Syndrome, possible explanations for these issues and makes some recommendations for interventions. The second paper is on sleep, using the overnight sleep apnea monitoring data collected during the last few years of the research clinic. This paper describes the high rate of obstructive apnea that we observed and discusses the potential importance of detecting and treating this symptom. A third paper is almost ready to be submitted; this one is on hearing impairment and how it changes over time in Wolfram Syndrome. Once these papers are peer reviewed and approved for publication we will certainly share them with all who are interested.
Second, Dr. Marshall and I are planning our trip to Paris for the International Wolfram meeting. I will be presenting on change in brain structures over time in Wolfram Syndrome, again using our Wolfram research clinic data. We are excited to learn from our Wolfram Syndrome research colleagues and see what progress the entire field has made since we last convened.
Finally, we have been talking with The Snow Foundation about submitting a grant to the NIH to fund a family/scientific conference on Wolfram Syndrome. The idea would be to bring in researchers and clinicians with relevant expertise on Wolfram Syndrome and present the latest information to other researchers, clinicians and families. As we start planning for this, we will be interested in hearing what families might be interested in learning at such a conference.
Thank you all for your interest and support.

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