Small Steps Towards a Bigger Future

The journey of one thousand miles begins with one step — Lao Tzu

A friend and former boss of mine told me when I started The Snow Foundation, that I can only ever take one step at a time. I keep this always in mind. As I reflect on the journey that God placed in my heart nearly eight years ago, I believe that the key to realizing success, not only for WS patients but also for those with diabetes and neurological diseases, is not to focus on the dream of a cure, but on the lessons learned along our way to it. This is what makes TSF so special.

Our foundation has grown in so many ways and continues to grow. Be assured that TSF is a constant partner to patients, families, researches and doctors as we work together in pursuing effective drug therapies.

This spring edition of the newsletter happens to be one of my favorites—it is full of pertinent and helpful information in regards to what is happening in the world of WS research.

As the Founder and Chair of TSF, I have learned to be content with small steps. When I look back on how far we’ve come, we’ve covered quite a distance. Thank you for continuing to believe in this mission, for your support, concern and compassion for our WS patients. You have my deepest gratitude.

Mitochondria and Wolfram Syndrome Research Trial

Proof of Concept study in Wolfram Mice- Mitochon Pharmaceuticals

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.

MANF and WOLFRAM SYNDROME

Amarantus Bioscience Holdings’ Chief Scientific Officer John Commissiong, PhD discovered mesencephalic astrocyte-derived neurotrophic factor (MANF) as a potential therapy for a range of conditions associated with protein misfolding and cell death, and the Company has begun development across several therapeutic areas. 

Amarantus has produced data in the areas of vision loss (retinitis pigmentosa, retinal artery occlusion and glaucoma), hearing loss (antibiotic-induced ototoxicity), metabolism (Type-1 diabetes) and neurology (Parkinson’s disease and Alzheimer’s disease). Amarantus has been collaborating with Dr. Fumihiko Urano since 2011 on the MANF program in the area of Wolfram’s-induced diabetes when he was at the University of Massachusetts, and expanded that collaboration with The Snow Foundation in 2015 at Washington University, St. Louis, to include Wolfram’s-induced vision loss and hearing loss. The Snow Foundation has funded and continues to raise money to fund MANF research.

Amarantus believes Wolfram Syndrome could represent a unique opportunity to develop MANF in a single patient population, but covering multiple aspects of the disease. They believe this has multiple advantages from a product development perspective in terms of speeding therapies to market for the smaller orphan indication Wolfram’s, but serving as proof of principle for larger indications such as diabetes. Amarantus recently formed a wholly-owned subsidiary called MANF Therapeutics, Inc. to exclusively focus on the development of MANF and to raise capital to bring it forward and is hiring management talent to advance this objective.

For further information on Amarantus please visit www.Amarantus.com, or connect with the Amarantus on Facebook, LinkedIn, Twitter and Google+.

Dr. Barrett’s Update

Dear friends and colleagues,

I wanted to update you about the TREATWOLFRAM clinical trial. Rebecca Storey, our clinical trials coordinator, has done a fantastic job in writing all the regulatory documents. These include things like patient information sheets, consent forms, ethics submission, clinical trial reporting documents, insurance and adverse event notification. She submitted the whole package in January. We had the ethics committee interview in February, the ethics approval in March, and last week we finally received the UK Health Research Authority approval letter. This means all the approval documents are in place! This has been a fantastic amount of work, and I am really grateful to Rebecca and the clinical trials team in Birmingham for pulling these all together. I am now sending the whole package to our partners in Spain, France, and Poland, so that they can get their own country regulatory approvals in place to start the trial.

The next rate limiting step is production of the medicine. As you know, we have had great difficulty in proving the medicine remains stable when outside its manufacturers’ packaging. Our pharmacy production unit at Guy’s and Thomas’s hospital in London have been working hard to find a method to prove stability; they have made some progress over the last 2 weeks. At the same time, I have been in touch with bulk medicines suppliers, who have found a couple of alternative sources of the medicine that come in old fashioned glass bottles. This could be interesting as the medicine could stay in its original container.

We have a telephone conference about this next week and I remain hopeful that we can solve this problem in the near future. I will keep you all updated through Tracy as soon as I have more information.

In the meantime, I am spending the next 2 days with Susan Gleeson meeting some wonderful families at our children’s Wolfram clinic here in Birmingham. I hope you all have a relaxing (and sunny) May bank holiday.

With best wishes

Tim

Wolfram Research Clinic Update

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.

Need Help?

For questions or requests regarding the Wolfram Syndrome Research Clinic please contact the WFS Research Clinic Coordinator, Samantha Ranck.

Accelerating clinical trials in Wolfram syndrome: development of efficacy biomarkers and patient relevant outcome measures

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.

Wolfram Syndrome and the Bladder – Part 1

Dr. Malcolm A. Lewis, MB ChB, FRCP

Consultant Paediatric Nephrologist, Children’s University Hospital, Temple Street, Dublin

Honorary Clinical Senior Lecturer, Royal College of Surgeons in Ireland

Wolfram syndrome is a genetic disease characterised by the slow development from childhood of optic atrophy (visual loss and eventually blindness), deafness, diabetes mellitus and diabetes insipidus (overproduction of dilute urine through deficient production of the hormone ADH that makes the kidney retain water). The underlying problem is thought to be the absence of or defective production of a protein called Wolframin.  Wolframin sits in a structure called the endoplasmic reticulum, present in all cells in the body, and is important for controlling the flow of calcium in and out of cells.  Failure of normal calcium control in cells leads to early cell death (apoptosis).  

As all cells in the body are affected by the defect many other problems occur with age in patients with Wolfram syndrome in addition to the diabetes insipidus (DI), diabetes mellitus (DM), optic atrophy (OA) and deafness (D) that gave it the original name of DIDMOAD syndrome.  Amongst the problems that occur are progressive bladder dysfunction.  These are important as they can lead to both socially disabling problems with continence and high bladder pressures causing kidney damage.

In this series of short articles, I will look specifically at the problems with bladder function experienced by patients with Wolfram syndrome.  It needs to be stressed at this point that, as with all other aspects of the disease, the effect on any individual is unique to them.  Not all the bladder problems seen in Wolfram syndrome are experienced by all patients.  Whilst, through these articles, I am providing an overview of what can happen with the bladder (and kidneys), for any individual a personal clinical history and examination by their paediatrician, physician or urologist is required to determine the appropriate interventions in their case.

I will divide discussion of the bladder into the following sections;

1.  An overview of normal kidney and bladder function.
2. The spectrum of problems of bladder function seen in Wolfram syndrome.
3. Monitoring of the bladder and kidneys of patients with Wolfram syndrome from childhood.
4. Therapeutic interventions for when functional bladder disorders arise in Wolfram syndrome.
5. Research and development in the management of bladder dysfunction with specific reference to Wolfram syndrome.

Figure 1.  Anatomy of the normal urinary tract.

1.  An overview of normal kidney and bladder function.

The normal urinary tract consists of two kidneys, one on each side, which receive a large blood supply from the main artery from the heart – the aorta (Figure 1).  This blood is filtered through about one million individual units called nephrons in each kidney (Figure 2).

Figure 2.  Schematic diagram of on of the one million nephrons in each kidney.

The filtered blood is returned to the circulation into the inferior vena cava.  The blood flow through the kidneys is one fifth of the heart output, about 1,000 ml a minute in an average adult.  This equates to 1,440 litres a day!  About 40% of the blood volume is made up of the red and white blood cells and platelets in our circulation.  This leaves 60% which is liquid or plasma.  As the plasma passes through the blood vessels in Bowman’s capsule of the nephron about 20% of the throughput is filtered to pass through the tubular system of the nephron.  This equates to 120 ml/minute in an adult.  With the constant filtration this leads to the production of about 172 litres of filtrate or urine as we know it.  None of us pass anywhere near that amount of urine in a day.  This is because as the urine passes through the length of the nephron most of the water and all the required salts are reabsorbed through the nephron wall and back into the blood stream.  This way we do not get dehydrated through loss of water and the amount of urine produced is decreased to a reasonable volume.  The fine control of water absorption determining the final urine volume takes place in the collecting duct at the very end of the nephron.  Here, under the influence of the hormone ADH, water is reabsorbed.  The more ADH, the more water is reabsorbed.  ADH production is dependent on how full our blood vessels are and how much we drink.  If we don’t drink and get dry a lot of ADH is produced.  If we drink lots, ADH production stops to allow this water to be disposed of as urine.  In Wolfram syndrome where DI has developed, ADH is deficient and consequent reduced or absent water reabsorption leads to excessive urine production (often 4 to 8 litres daily).  As a result, patients need to drink excessively to prevent dehydration.

The urine produced passes from the kidney down a fine muscular tube called the ureter, into the bladder.  The bladder is a muscular bag (detrusor muscle) to store urine with a valve system (internal sphincter, external sphincter and pelvic floor muscles) at the bottom end to prevent leakage.  In the resting state the detrusor muscle is relaxed and expands easily.  The sphincters are tight to prevent any leakage.  As urine is produced the bladder steadily fills.  Nerves in the bladder send messages back to the brain to say that the bladder is stretching.  In babies this message leads to an automatic, coordinated contraction of the bladder muscle and relaxation of the sphincters so that the bladder empties.  Older children and adults can consciously override the instructions from this message to keep the detrusor floppy and the sphincters tight until an appropriate time.  At the appropriate time individuals can then induce synchronised detrusor contraction and sphincter relaxation, to allow low pressure evacuation of the bladder into an appropriate receptacle (Figure 3.)

Figure 3.  The normal cycle of bladder filling and emptying

Next time: The spectrum of problems of bladder function seen in Wolfram syndrome.

Global Website and Patient Registry

The Snow Foundation is excited to announce our plans to establish a global Wolfram Syndrome website. This site will serve the WS community and have no borders. It will be an online social hub dedicated to patients, families and healthcare professionals affected by WS. The site will provide:

• A forum to help individuals connect with each other
• Medical information (e.g., understanding a WS diagnosis)
• A list of doctors, specialists or clinics with experience in diagnosing or treating WS
• A patient-powered registry, which will help advance medical research
• Research and clinical trial updates
• Much more!

We expect to roll out the new global website spring 2019.

The Beginning of a New Era for Gene Therapy and Blindness

Jason Comander, M.D., Ph.D., in surgery at Mass. Eye and Ear. Credit: Massachusetts Eye and Ear

Massachusetts Eye and Ear performs first FDA-approved gene therapy procedure for inherited disease

Become a Monthly Donor

Over 7 years ago, the Snow Foundation began the fight of a lifetime. Together we can finish that fight. Support TSF and become a monthly donor and help us put an end to Wolfram Syndrome.

It’s the easiest way to give and ensure that The Snow Foundation receives your ongoing support. Your recurring monthly donation means, together, we will help put an end to this horrible disease.

Visit the link “Become a Monthly Donor” and click on the box to Make this a monthly donation.

How about sweet notes to friends and family that will benefit The Snow Foundation? Make them original and special with your custom note cards. Create personalized stationary and always have a notecard on hand. Whether you’re writing a thank you note, a get-well message or a last-minute birthday greeting. Never purchase a boring card again!

For more information please contact Andrea Warner at andiw222@gmail.com
or visit her Etsy Shop: ArtvsWolframSyndrome