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

Association for Wolfram Syndrome + Eye Hope Foundation + The Snow Foundation logos

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. 

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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.
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Wolfram Research Clinic Update – May 2018 – Tamara Hershey, PhD

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

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Prof Tim Barrett Clinical Trial Update-Birmingham, England

Rebecca Storey and Shazia Ahmed, our senior and junior trials coordinators respectively, have been busy writing all the regulatory documents needed for the trial to go ahead. These were submitted to the Health Regulatory Authority in early January. The ethics committee met in early February. This was in Glasgow, but we were allowed to join by telephone conference. the committee was very sympathetic and had only minor requests. Rebecca and I are writing the response, which has to be back with them by Wed. We cannot get complete regulatory sign-off until we have evidence that the study medicine is stable outside it’s manufacturer’s packaging.

Regarding the study medicine, we have been in weekly contact with the pharmacy manufacturing unit at Guy’s and Thomas’s Hospital in London. They have outsourced the testing of the medicine to a commercial contract company, Butterworth’s. So, the problem is that the study medicine comes in foil blister packs. The manufacturer only guarantees the quality of the tablets while they are in their own packaging. For the clinical trial, Guy’s and Thomas’s Pharmacy have to take the tablets out of the manufacturer’s packaging and put them into white polypropylene containers, so that they can be masked (blinded) with the placebo tablets. Unfortunately, these study tablets absorb moisture from the atmosphere when taken out of their foil packaging, which in theory may affect the stability of the active component. Guy’s and Thomas’s hospital have been trying to test some tablets that they have kept in typical study bottles; but without success. They then outsourced this job to Butterworth’s, who found a non-standard method to measure drug stability. However, when they tried to convert this to an approved method, they could not get the measurements to work. This is turning into a major headache, and is the reason the study has been held up. We are having a telephone conference on Monday with the pharmacy team to get an update and plan what we do next.

We have appointed a new study team member, Heather Rose, who will look after the MRI scans for the trial, and do the measurements to see if the study drug is slowing down the brain changes. She is getting the scanners set up in Birmingham for both children and adults to take part.

Rebecca has been in touch with the international sites, in Almeria, Montpellier, Paris and Lodz, to start getting them set up.

Finally, I have been asked to speak with the French families in Paris on March 17th to explain to them where the trial is at.

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Dr. Urano’s April Update

Dear Friends,Fumihiko “Fumi” Urano, MD

Thank you so much for “coming to see me” today. It is always my pleasure and privilege to see you and talk to you. I feel your support and encouragement, and I am grateful for everything you have done for me, the Snow Foundation, patients, and their families and friends. Just reading this blog is helping me because I can feel your support, which makes me feel stronger and committed.

I would like to share my ideas on how to provide a cure for Wolfram with you today as our first clinical trial is ongoing and we are making steady progress in the development of new drugs, regenerative therapy, and gene therapy. I have been thinking and presenting my strategy for therapeutic development of Wolfram syndrome, CURE4WOLFRAM, since 2002. My current version, 4.0, is the following.

1. Stop Progression

ER Calcium Stabilizers
One of the common molecular pathways altered in patients with Wolfram syndrome and diabetes patients is imbalanced cellular calcium homeostasis. More specifically, endoplasmic reticulum (ER) calcium levels are lower in patients with Wolfram syndrome, leading to cell dysfunction and death. To overcome this challenge, we are currently testing if an ER calcium stabilizer, dantrolene sodium, can delay the progression of Wolfram syndrome. Dantrolene sodium is a FDA-approved drug for the treatment of muscle spasticity and high fever induced by anesthesia. We previously reported that dantrolene sodium stabilizes ER calcium levels and prevents cell death in cell and mouse models of Wolfram syndrome. We are currently conducting a clinical trial of dantrolene sodium in adult and pediatric patients with Wolfram syndrome. In collaboration with NIH/NCATS, we are also developing novel ER calcium stabilizers (i.e., second generation dantrolene) for the treatment of Wolfram syndrome.

Molecular Prosthetics
Another common issue in patients with Wolfram syndrome is ER stress caused by the expression of mutant Wolfram protein produced in patients’ cells. To resolve this issue, we have been developing molecular prosthetics that can optimize the structure of mutant Wolfram protein together with NIH/NCATS and Amylyx, a biotech company in Cambridge, MA.

2. Protect and Regrow Remaining Tissue

Our second step towards a cure for Wolfram syndrome is to protect and regrow remaining tissue using regenerative therapy. We have discovered a naturally produced molecule in our body that can activate the proliferation of damaged beta cells and brain cells. Expression levels of this molecule, MANF, are usually low in our body. We are developing a method to enhance the activity of MANF using a pill that can mimic the functions of MANF and gene therapy (i.e., produce safe virus expressing MANF).

3. Replace Pathogenic Genes

Towards a cure for Wolfram syndrome, a genetic condition, we need to target the root cause of the disease, which is the loss of function of Wolfram syndrome gene, WFS1. Using CRISPR/CAS9 technology, we are attempting to replace a pathogenic Wolfram gene (WFS1 gene) with a healthy Wolfram gene. We are also trying to introduce safe virus expressing normal WFS1 gene into patients’ cells.

Thank you so much for being with me today. Good things happen to people who do good things. I am always hopeful.

With grace and gratitude,
Fumi Urano

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The British Journal of Occupational Therapy

“Understanding activity participation among individuals with Wolfram Syndrome”

2018 has brought another publication from the Wolfram Research Group! This article, titled “Understanding activity participation among individuals with Wolfram Syndrome”, was recently accepted to the British Journal of Occupational Therapy.

We wanted to learn more about the use of Occupational Therapy (OT) services in people with Wolfram Syndrome (WFS), and how participation in daily activities could be affected due to WFS symptoms. Participation in daily activities means being able to do the things we want and need to do, which leads to more independence and improved quality of life. Knowing the activities that are most important to those with WFS can help us develop better and more patient-focused interventions and services.

We asked research clinic participants questions about 1) their use of OT services in the past and present, 2) which daily activities were most difficult for them to accomplish, how important these activities are to them and how satisfied they were with their performance and ability to do the activity, and 3) which WFS symptoms affected these daily activities.

Overall, we found that only 22% of participants have ever used OT services. These services were most often for fine motor coordination and low vision. In addition, we found that daily activities identified as important were self-care (personal care, mobility), productive (household management, going to school or work), and leisure (recreation and social) activities.

Overall, we found that people reported reduced participation in daily activities when compared to a non- WFS group. In addition, participation was more restricted over time as WFS neurological symptoms progressed. Adults had more difficulty with activities that were related to social activities and getting out in the community and children/teenagers had more difficulty with activities related to playing and school. Participation in daily activities was most restricted due to walking/balance problems and loss of vision.

These findings raise awareness of the impact of WFS symptoms on daily life and point to neurologic and vision symptoms as being the most limiting aspects of WFS. OT professionals can provide self-management techniques and strategies for low vision or balance issues. These approaches may be of help to those not already using OT services.

 

For more information, look for this publication in the near future: Bumpus E, Hershey T, Doty T, Ranck S, Gronski M, Urano F, & Foster E. Understanding activity participation among individuals with Wolfram Syndrome. British Journal of Occupational Therapy. (In Press).

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Washington University School of Medicine 2018 Wolfram Research Clinic Update

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

Yes, we’re still waiting! No word yet on the final determination of funding for the 2018 Wolfram Research Clinic. But, as we said, we are proceeding with the planning. We wanted to share with you the final dates of the clinic and a couple of changes from previous clinics.

The official clinic dates are Wed., 7/11/18 thru Wed., 7/18/18. The way it will work is that we’ll have two groups thus two clinics; Clinic 1 and Clinic 2. Clinic 1 will be held Wed., 7/11/18 thru Sun., 7/15/18. Clinic 2 will be held Sat., 7/14/18 thru Wed., 7/18/18. Testing will take place on week days and the Wolfram Group meeting (formerly known as the “Saturday Session”) will be held on Saturday, 7/14/18. The change most frequently requested by the families on the post-clinic evaluations is more time built in to the schedule for families to socialize. In an effort to meet this request, we are working on setting up family socials at least one night during each clinic and one after the Wolfram Group meeting on Saturday. It will take a bit to find a space that fits our group but we want you to know that we heard your request and we’re working on it!

Dates to remember:

Clinic 1 – Wed., 7/11/18 – Sat., 7/14/18 Wolfram Group meeting & Family Social – Sat. 7/14

Clinic 2 – Sat., 7/14/18 – Wed., 7/18/18

If you have a preference of attending Clinic 1 or Clinic 2 please let Samantha know sooner rather than later!

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

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What are biomarkers and why are they important?

January 2018 

One of the global health priorities of the International Rare Diseases Research Consortium (IRDiRC, www.irdirc.com) is on to find new treatments for the 80% of rare diseases that currently have no cure or means to treat. We know of over 8,000 rare diseases, so this is a really big challenge. As everyone knows, it is a huge task to come up with a treatment, then get it approved so that patients can have it in the clinic. Once you have come up with a treatment, people ask: ‘how do you know it will work?’.

The best example I can think of is anaemia. You may be feeling tired and pale with a lack of energy, and go to your doctor – she takes a blood test, tells you that you are anaemic, and prescribes you some iron medicine. You take the medicine, and after a few weeks you feel better so your doctor invites you back for another blood test, says your blood count has come up, and you can stop the medicine. That blood count is what we call a ‘biomarker’ – something that we can measure to see if a treatment has worked. The doctor needs it to decide when to tell you to stop taking your medicine. Without it, she doesn’t know whether you feel better because the medicine worked, or because you are eating better, or just because the sun has come out!

A biomarker is anything that we can measure, to see if a treatment is working. If the treatment is to help you lose weight, the biomarker is your weight. If you have a metabolic problem where a toxin builds up in your blood, then the biomarker is the level of toxin in your blood. It can even be a change seen on X-ray or brain imaging scan.

Biomarkers become especially important when you are treating a disease that takes months or years to progress- if you start taking a treatment, you want to know it is helping you, without waiting for years to find out if you are going to develop any complications of the disease.

When we study a medicine to see if it will treat a disease like Wolfram, it may take at least two years, or probably longer, to tell if the medicine has stopped the disease getting worse. If after 2 years, the person’s disease is still getting worse, then the medicine has not worked, and he/she has to start the process from the beginning with another treatment.

You might ask – why not try several different treatments at once? That’s a good question but there are two problems: firstly, the treatments may not work; or only one of them may work and the others are unnecessary; and then every treatment has side effects, which may get worse when you mix them with other medicines.

So why might biomarkers help? Well, to use the example of anaemia again: if you have something that you can measure, like a blood count in anaemia, you can quickly find out if the treatment is working, even before the person who was anaemic feels any better.

In Wolfram, if we ask people to take a treatment for the disease, we want something we can measure that will tell us quickly whether the treatment is working or not, without having to wait 2 or more years to tell if the disease has stabilised.

Biomarkers become really useful in clinical trials of a treatment: we really need a biomarker that will tell us whether the treatment is working within 6 months; so that if it is not, we can stop the trial, and switch to another treatment.

This is why we will be asking people to donate blood samples during our upcoming clinical trial. We want to make the samples available for the wider research community, and support the international effort to find biomarkers to measure the effectiveness of treatments in Wolfram.

Tim Barrett 

the-british-consortium

The consortium Left : prof. Timothy Barrett, Right, 1st line: prof. Melanie Calvert, Dr Kristian Brock, Dr Zsuzsanna Nagy Right, 2nd line : prof. Richard Sinnott, Dr Anita Slade, Dr Ben Wright

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Dr. Urano’s January 2018 Update

Fumihiko “Fumi” Urano, MDHello Everyone,

As this is the first time to see you in 2018, I would like to begin by thanking all of you for your continued support and encouragement. I appreciate it immensely. I am so grateful to have such supportive friends. I would like to update you about our latest developments as usual.

Our drug-repurposing clinical trial of dantrolene sodium is ongoing. The trial began in January 2017. Twenty-two patients with Wolfram syndrome enrolled. Two patients decided to leave the study due to personal reasons and one patient could not start the study because of medical reasons. So nineteen patients started taking dantrolene sodium. As of today, fifteen of them have been taking dantrolene for more than 6 months. At this stage, my team has found few side effects and has identified safe dosage levels in adult and pediatric patients. I saw some beneficial effects on remaining beta cell functions, visual acuity, and neurological functions in some patients, but did not see any beneficial effects in other patients. Because all the participants are taking dantrolene, we cannot conclude that any effects are due to dantrolene. Nevertheless, I have sent the data of fifteen patients to statisticians who have not been involved in our Wolfram studies (myself and my colleagues are biased as you can imagine). We will find out more about the outcome of this study in the next several months.

I thought a lot about our therapeutic development for Wolfram syndrome during the holiday season. I feel that drug-repurposing may not be good enough. I firmly believe that we need a breakthrough therapy for Wolfram syndrome. This year, I would like to spend more time for developing regenerative gene therapy, especially for visual impairment. In parallel, I would like to develop a second-generation dantrolene which is more potent and safe. These are my two goals in 2018.

I feel that something new and wonderful will happen to us this year. I feel that we will go into a new stage. Thank you again for your continued support. I am hopeful and grateful.

Looking forward,

Fumi

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Dr. Urano’s November Update

November 4, 2017Fumihiko “Fumi” Urano, MD

Dear Friends,

It has been a while since we last talked. I hope you are enjoying this Fall season with your family and friends. I think about the value of family and friends a lot lately. Support from family and friends keeps me going. So I appreciate your continued support, encouragement, and kind words. Let me update your about our progress on therapeutic development for Wolfram syndrome.

Our drug-repurposing clinical trial of dantrolene sodium is ongoing. The trial began in January, and nineteen patients with Wolfram syndrome from the US and Canada are now involved. Participation requires periodic testing and monitoring at the adult and pediatric clinics at Washington University Medical Center in St. Louis.  The trial is focused on the safety, tolerability, and efficacy of the drug (visual acuity, neurological functions and remaining beta cell functions). At this stage my team has found few side effects and has identified safe dosage levels. More tests and data are necessary before any conclusions can be reached.

I am aware that we need a breakthrough therapy for Wolfram syndrome. In theory, drugs that target endoplasmic reticulum (a cellular compartment damaged in Wolfram patients), such as dantrolene sodium, can delay the progression and may improve functions of remaining beta cells and brain cells, but these drugs cannot reverse symptoms. We need something that can reverse symptoms, such as visual impairment, and we need to tap into new technologies. We are developing a regenerative gene therapy, especially for visual impairment. Our strategy is to introduce a regeneration factor into a type of retinal cells using a gene transfer technology. This is clearly not simple and requires a lot of time and efforts, but we are making progress.

Thank you for taking your time to read my blog. I hope to talk to you again soon.

Warmest regards,
Fumi Urano, MD

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