September 22, 2017
Dear Friends,
It is nice to “meet” you again. Thank you for your generous and continued support for our therapeutic development for Wolfram syndrome. With the support from the Snow Foundation, multiple patient organizations and supporters around the world, and federal grants, I could maintain the Wolfram syndrome program to study the disease, which led to fundamental laboratory studies that uncovered the molecular genetic defect, and ultimately to the identification of a therapeutic target that is now being tested in patients. Our first clinical trial of a re-purposed drug, dantrolene sodium, in patients with Wolfram syndrome is ongoing. We have been monitoring the safety, tolerability, and efficacy of dantrolene sodium in 21 patients who have qualified for the study. You can find the information about the inclusion and exclusion criteria on the following website. We have both male and female participants in pediatric and adult populations. https://clinicaltrials.gov/ct2/show/NCT028292680
The planned duration of oral dantrolene sodium administration in this study is 6 months with an optional extension phase up to 24 month. All the participants are required to come to our clinic 9 times in the first 6 months to determine the appropriate dose and ensure the safety. After the first 6 months, participants come to our clinic every 6 months up to 24 months. As of today (September 22, 2017), 20 participants are taking dantrolene sodium and one participant has left the study due to personal reasons. 9 out of 20 patients have been taking dantrolene sodium for more than 6 months. In addition to safety and tolerability, we have been assessing our participants’ visual acuity, remaining beta cell functions (i.e., their ability to produce insulin from their own pancreases), and neurological functions every 6 months. We plan to publish the data once we collect the information from these 20 participants after the 6-month administration of dantrolene sodium.
On a different note, Senator Roy Blunt and the Director of National Center for Advancing Translational Sciences (NCATS), Dr. Christopher Austin (https://ncats.nih.gov/), visited our medical center last month. I had a chance to present our medical center’s efforts on rare disease therapies. I am glad to tell you that our presentations were perceived really well. Stephanie and I met with Dr. Austin a few years ago at the NCATS headquarter in Bethesda, close to Washington DC, and that was the beginning of my collaboration with the drug development team at NCATS. We will keep on working together for developing rare disease therapies.
Thank you for being with me. I plan to update you about our two new drugs and regenerative gene therapy for retinal degeneration in my next blog. I hope you will have a wonderful fall season. See you soon.
Warmest regards,
Fumi Urano, MD
Dr. Fumihiko “Fumi” Urano, MD
Dear Friends,
I hope you had a wonderful summer season. I would like to update you about our progress.
Our clinical trial of dantrolene sodium in patients with Wolfram syndrome is ongoing. We have been monitoring the safety, tolerability, and efficacy of the drug. Some patients have been taking dantrolene sodium for more than 6 months, and we have started getting the safety, tolerability, and efficacy data. We plan to publish the data once we collect the information from 20 patients. I have started preparing for the next phase of this trial. As I mentioned in my previous blog, we are considering the following possibilities.
- A longer duration, More participants, Multi-center
- Include the placebo arm. I understand that nobody wants to take the dummy drug for a long period of time. So I have been getting advice from medical officers conducting clinical trials for rare diseases.
In addition to dantrolene sodium, my team has been looking into two new drugs for Wolfram. Unlike dantrolene sodium, these drugs are new. So we need to carefully collect more data from mouse models of Wolfram and healthy human subjects.
- The first drug is an endoplasmic reticulum (ER) calcium stabilizers which we discovered together with NIH/NCATS. This drug is for delaying/halting the progression of the disease. Pre-clinical studies in mouse models of Wolfram are ongoing.
- The second drug is a chemical chaperone which reduces ER stress. We have started collaboration with a biotech company on this new drug.
I am aware that we need to find a way to improve visual acuity. I am trying to secure funds for testing our new regenerative gene therapies for optic nerve degeneration using a novel neurotrophic factor in combination with gene transfer technology. I have applied for multiple grants and am quite hopeful about the outcome.
Thank you for your continued support. I cannot thank you enough.
Take care,
Fumi Urano, MD
Professor Patrick Yu-Wai-Man
Affiliations
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge
- MRC Mitochondrial Biology Unit, University of Cambridge
- Cambridge Eye Unit, Addenbrooke’s Hospital, Cambridge University Hospitals
- Moorfields Eye Hospital and UCL Institute of Ophthalmology, London
I am an eye doctor (ophthalmologist) with a particular interest in genetic eye diseases. I look after patients with Wolfram syndrome in my specialist clinic and I also lead a research group that is investigating ways of slowing or preventing loss of vision in patients affected with this relatively rare genetic disorder.
How is visual information sent from the eye to the brain?
The eye is a very sensitive camera that converts an image from the outside world into an electrical signal. At the back of the eye is the optic nerve, which is similar to a high-speed “broadband cable” that allows this electrical signal to be sent quickly to the vision centres at the back of the brain to be decoded. The figure above illustrates how visual information gets from the eye to the brain via the connecting optic nerve.
What is optic atrophy?
The majority of patients with Wolfram syndrome will develop optic atrophy. Optic atrophy means that the optic nerve has been damaged and it looks pale in colour when the eye doctor looks at the back of the eye with the appropriate equipment. Because the optic nerve is damaged, less visual information is sent from the eye to the brain, and this also happens more slowly with transmission errors. As a result, patients with Wolfram syndrome start to struggle with their central vision and they find it increasingly difficult to read small print and make out people’s faces (as in the example shown below). Visual difficulties usually start in childhood and they tend to get progressively worse with time.
What other eye problems can you get in Wolfram syndrome?
- Diabetes is very common in Wolfram syndrome, but fortunately diabetic eye complications tend to be rare. Nevertheless, patients with Wolfram syndrome need to take particular care that their blood sugar levels are well controlled to avoid further diabetic eye complications in addition to optic atrophy.
- A small group of patients with Wolfram syndrome can develop cataracts at a young age. If the eye doctor spots that a cataract is present and vision is getting worse because of it, the option of cataract surgery can be discussed.
What treatments can we offer at the moment?
- Unfortunately, there is currently no proven treatment to stop the damage to the optic nerve and loss of vision. There is a lot of research being carried out at the moment to look for drugs that can protect the optic nerve. Gene therapy is also being considered, but this strategy is still an early stage of development and so far, studies have only been carried out in mice.
- As there are no effective treatments yet for the optic atrophy in Wolfram syndrome, visual rehabilitation is very important and children, especially, must be provided with the right level of support at school.
How frequently should an eye check-up be carried out?
All patients with Wolfram syndrome should ideally have an annual check-up. Drops will usually be put in the eyes to dilate the pupils and make it easier to have a careful look at the back of the eye for any changes since the patient’s last visit.
Dear Wolfram Families and Supporters:
The Washington University Wolfram Research Clinic (or ‘natural history) study just finished its 8th consecutive year of assessing patients with Wolfram Syndrome. This work began in 2010, supported in part by the Snow Foundation. For the past 5 years, it has been supported by a National Institutes of Health grant in Dr. Hershey’s lab (Tracking Neurodegeneration in Wolfram Syndrome; Hershey, Principal Investigator). The focus of this grant is on understanding the neurological changes that may occur over time in Wolfram Syndrome, including the function of the brain (e.g. vision, balance) and the structure of the brain (e.g. the volume or integrity of different regions of the brain).
This year, we focused on assessing new patients, and those who had only been seen once or twice before. We hosted 9 families from all over the country and performed 106 exams and 8 MRIs. This clinic was smaller than previous years due to limitations in funding and the ongoing Dantrolene safety study. However, this focus allowed us to increase our understanding of how symptoms change over a 2 year time period, which are critical data for planning and implementing clinical trials. Altogether, over the past 8 years, we have assessed 40 unique individuals with Wolfram Syndrome and their families, some up to 7 times.
Just weeks before the clinic, we got the good news that our request to extend this work for another 5 years was reviewed very favorably! We received a score which should ensure that we get the funding we need, but will only know for sure this fall. In anticipation, we are going to start planning for next summer’s research clinic soon and hope to open it to anyone who has been seen in the past or any new patients that come to our attention. We will work together with Dr. Urano on any ongoing drug safety or efficacy studies to make sure that families do not have to choose between studies and that each study can support the other’s goals.
As always, we will keep you up to date with our WU Wolfram Research Clinic newsletters, the Snow Foundation newsletters, our website (http://hersheylab.wustl.edu) and emails or calls. Please contact any of us at any time if we can provide more information or assistance! We would love to hear from you!
Thank you!
Tamara Hershey, Ph. D.
Professor & Principal Investigator,
WU Wolfram Research Clinic
Bess Marshall, MD
Pediatric Endocrinologist & Research Clinic Medical Director
Samantha Ranck, MSW
Research Clinic Coordinator
314 362-6514
rancks@npg.wustl.edu
Dear Friends and colleagues,
I would like to give you an update as to progress with our clinical trial of a treatment for Wolfram syndrome.
We had the final confirmation of funding from the UK Medical Research Council on December 16th 2016, so were able to start work on the study protocol early in the New Year. We were fortunate to have Ms Rebecca Storey appointed as Senior Trials Coordinator in January. She has lots of experience in running clinical trials, and is based in the Clinical Trials Unit, University of Birmingham. She hopes to attend the family conference in October, so I hope some of you will meet her.
We then appointed local lead investigators for the UK: this will be Dr Renuka Dias for the children’s hospital clinic, and Dr Ben Wright for the Queen Elizabeth Hospital adult clinic. Also in January, Tracy kindly met with me at my parents’ house near Gatwick Airport, where we discussed what the clinical trial would look like, and what to include in the participant information sheets. The main point was that families would prefer partipants to have an increased chance of receiving the study medicine rather than the placebo. I took this back to our trial statistician Kristian Brock, who has been able to include this request. Participants will now have a 2:1 chance of being given the study medicine rather than the placebo. Kristian Brock is an expert in statistics and trial design, and will also try to attend the family conference.
In February we started discussions with Guy’s and Thomas’s Pharmacy manufacturing unit to prepare the medicine and placebo. We also prepared the ethics application form, and had a telephone conference with our international partners in Spain, France and Poland.
In March I went to our local Young Persons’ Advisory Group. This is a group of 11-23 year olds, who kindly volunteer to read study information and critically appraise it so that it is readable and easily understood. I took them the participant information sheets I had prepared, and I am sorry to say they looked them over very critically! They pointed out that the layout could be improved; that there was some repetition; and that a glossary of medical terms would help. I am very grateful to them and the information sheets are now shorter and clearer to read.
In April I attended the European Medicines Agency in London with Julie Warner, from Boyd Consultants, who provide regulatory advice. They agreed that we must check if the treatment slows the rate of deterioration of vision; however they would like a second outcome measure that is important for families. We are now working with experts on patient reported outcome measures, and would like to propose some ideas to you – things to measure which are important for a treatment to improve.
I also visited the French Wolfram association in Paris, just before Easter, and attempted to present the clinical trial in French. The audience was very polite and tolerated my schoolboy French! In May I gave a similar presentation to Spanish families in Almeria, hosted by Dr Gema Esteban, our Spanish collaborator. There is a lot of enthusiasm to take part, and there were many questions. Some of these related to randomisation, and I had to explain that the European Medicines Agency insist that some people receive the medicine and some the placebo. This is in order to provide the strongest evidence that our medicine works.
We are now hoping to sign the contract with the pharmacy manufacturers; submit the ethics application package in September; and recruit the first participants in the UK at the end of November. The timescale has been extended as we have to show that the medicine is stable outside the manufacturer’s packaging, when we put it in airtight plastic containers. This stability testing started last week, and takes 3 months.
Later this month, we have a local investigator meeting, where we will sort out the practical aspects of what tests we will be asking participants to have. I would like to write another update at the beginning of July when I can feed back on this meeting.
Please don’t hesitate to get in contact if I can help at all with any questions. Meantime, thankyou all for your kind interest and support!
Sincerely
Prof Tim Barrett
Dear Friends,
It’s a spectacular Saturday morning in Saint Louis as I write this to you. I always appreciate your continued support, encouragement, and kind words.
I have received many questions regarding our ongoing clinical trial, as well as questions related to our next step lately.
Although we don’t have a concrete plan yet, we consider the following possibilities.
- A longer duration, More participants, Multi-center
- Compare the efficacy of dantrolene sodium, valproic acid, and dantrolene sodium plus valproic acid
We are also developing breakthrough treatments for Wolfram syndrome as dantrolene and valporic acid are old drugs originally developed for other medical conditions.
Here are our new plans.
- We have been developing a new drug designed for Wolfram syndrome (ER stress stabilizers) together with NIH/NCATS to delay/halt the progression of the disease. Pre-clinical studies in mouse models of Wolfram have been designed. We are seeking funds to complete these studies.
- Regenerative therapies using a novel neurotrophic factor in combination with gene transfer technology for visual impairment have been designed. We are seeking funds for testing these new therapies in mouse models of Wolfram syndrome.
I think we are making progress, and need to speed up as we are racing against time. Thank you again for your support.
Take care,
Fumi Urano, MD
Dear Friends and colleagues,
I have been fortunate to visit the French Wolfram Association meeting in April in Paris; and the Spanish Wolfram association meeting in May in Almeria.
I was humbled by the friendship and community spirit of these families; and they were very tolerant of my poor French and Spanish language skills.
On the research front, we have just published the online mutation database of genetic variants in the Wolfram gene. This was work undertaken by Dr Dewi Astuti, and is a freely available database to support scientists worldwide. The database is available at: https://lovd.euro-wabb.org
Regarding the Phase II clinical trial, we are negotiating manufacture of the investigational medicinal product and placebo. We hope to complete this in the next 4 weeks and are still aiming to begin recruitment in the UK in November.
Thank you for all your interest and support, and I will try to provide regular updates on our progress
Sincerely,
Prof Tim Barrett
Part 3: My Fight Continues – Pat Gibilisco
Part 3: My Fight Continues – Pat GibiliscoMoney was the only reason my child was not able to receive the drug that would potentially save her life. The Snow Foundation, or I should say Stephanie Gebel, worked so hard to raise money for all children affected with WS. She had to beg people, year after year, to continue to support the WS Foundation. I can tell you that was not an easy task! She had some support from the other families with WS, but not enough. Some families felt it was just too hard to ask for contributions. For 18 years, I have done everything I could to fight for all WS children. I repeatedly asked my family and friends to help me save my daughter. They were so generous in their efforts to help me find a cure for WS. Now I have to say that as much as I so appreciated their love, support and financial assistance, it was just too late. The father from Utah also lost his five children afflicted with WS.
Why does money always stands in the way of a cure? Could we have had more help from our WS group? Absolutely. I can tell you that the Snow Foundation has fought for ALL the WS children. Stephanie Gebel has fought to save her child’s life and every other family’s child. Dr. Fumi, Dr. Naseer, Dr. Hershey, Dr. Hoekel, Dr. Marshall, Dr. White, Dr. Paciorkowski, Samantha, Beth, Cris, and all the other medical professionals and staff have fought hard to save our children.
Am I mad? Yes. Am I bitter? No. Would I have done anything differently? No. It all comes down to money. Now it is too late for a drug to save my daughter. We started this fight 18 years ago, and it was ending for my daughter. No more clinical trials and no more clinics. My daughter is now totally blind and almost deaf, and she has bowel and kidney problems, seizures, choking episodes, heat intolerance, poor balance, Diabetes, Diabetes Insipidus, short-term memory loss, and many more issues that she deals with daily. All the while though, she has such a smile on her face and soul. Lauren and all the other past and present WS children are the real heroes. They are amazing kids.
For a fourth time, I will cry. It will be at her funeral. It will happen. Nothing can stop the clock from ticking. I can tell you I will NEVER quit until a cure is found. I will continue the fight so no other family has to go through the heartache I have. Please, I beg you, continue to fight the fight. Do not let money come between your child and a cure. We must save all the WS children. I don’t want another family to watch their child slowly die from the inside out. It is brutal to watch.
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