,

Researchers launch first clinical trial for Wolfram syndrome

The drug dantrolene is a muscle relaxant approved to treat patients with cerebral palsy, multiple sclerosis and muscle spasticity. Recent research also suggests it can prevent the destruction of insulin-secreting beta cells in animal models of Wolfram syndrome. Researchers at Washington University School of Medicine in St. Louis are beginning a clinical trial to assess the drug as a treatment for patients with Wolfram syndrome.

The drug dantrolene is a muscle relaxant approved to treat patients with cerebral palsy, multiple sclerosis and muscle spasticity. Recent research also suggests it can prevent the destruction of insulin-secreting beta cells in animal models of Wolfram syndrome. Researchers at Washington University School of Medicine in St. Louis are beginning a clinical trial to assess the drug as a treatment for patients with Wolfram syndrome.

 

Researchers at Washington University School of Medicine in St. Louis are launching a new clinical trial to assess the safety of a drug treatment for patients with the rare disease Wolfram syndrome.

Wolfram syndrome affects about one in every 500,000 people worldwide. Many of those patients die prematurely from the disease. Patients with Wolfram syndrome typically develop diabetes at a very young age and require insulin injections several times each day. The disorder also causes hearing loss, vision problems and difficulty with balance.

Although doctors treat patients’ symptoms, there have not been any therapies that slow the syndrome’s progress.

However, researchers at Washington University School of Medicine soon will test a drug treatment in 24 patients who have the genetic disorder.

The scientists previously reported in the Proceedings of the National Academy of Sciences that the drug, dantrolene — a muscle relaxant approved to treat patients with cerebral palsy, multiple sclerosis and muscle spasticity — prevents the destruction of insulin-secreting beta cells in animal models of Wolfram syndrome and in brain cells differentiated from skin samples taken from patients with the illness.

“Nobody has ever tested dantrolene in patients with Wolfram syndrome, so our first and most important objective is to make sure it’s safe,” said principal investigator Fumihiko Urano, MD, PhD, the Samuel E. Schechter Professor of Medicine. “I am very hopeful, however. The major question that I get from every patient I see is, ‘Is there any treatment?’ And until now, I’ve had to say no. With any luck, perhaps this study can help change that.”

In the mouse studies, and in experiments with brain cells made from a patient’s own stem cells, Urano previously found that dantrolene prevented death of brain cells and insulin-secreting beta cells.

Urano’s team plans to study 12 adult and 12 pediatric patients over nine months. All of the participants will undergo extensive testing before they begin taking the medication and after having taken the drug for six months. The researchers will closely monitor patients’ vision and brain function, as well as the function of their remaining insulin-secreting beta cells.

To be eligible for the study, all patients must be able to travel to the Washington University Medical Campus for testing and medication.

The study is funded by the Snow Foundation and the Ellie White Foundation. Both are advocacy groups that support Wolfram syndrome research. Urano also has applied for federal funding to support the clinical trial and wants to expand it to other medical centers.

He doubts that dantrolene can reverse the illness. “But hopefully, we can at least delay the progression of the disease,” he said.

For more information, call study coordinator Ashley Simpson at 314-286-1550, or e-mail ashley.simpson@wustl.edu.

 

Article by Jim Dryden

/by

The Snow Foundation: Fighting for a Cure

581cde770ce1f-image

Wolfram syndrome afflicts only about one in 500,000 people, but a local organization is doing everything it can to bring the numbers down and find a way to cure this incurable disease.

As described on The Snow Foundation’s website, Wolfram syndrome is an autosomal recessive genetic disorder that starts with insulin-dependent diabetes in early childhood. Unlike with common types of diabetes, these children go on to develop blindness, deafness and other neurologic disturbances. Since there’s no cure for the disease, more than 60 percent of patients die before the age of 30.

The Snow Foundation’s dedication to research has led the group to a new and exciting stage: the first-ever worldwide clinical trial for Wolfram syndrome. For the past few years, the foundation’s researchers have been focused on pre-clinical testing, but after receiving unconditional institutional review-board approval, they are now ready to begin clinical testing. Dr. Saad Naseer, chief executive and chief medical officer of the foundation, says all the money from charitable donations is paying off.

“We plan on beginning the clinical trial in January,” he says. “All patients will receive the same dose of the same medication and will be monitored in the same manner. The patients will serve as their own control.”

Naseer notes that if the foundation can figure out a treatment for this form of diabetes, the treatment will be able to help all forms of diabetes.

“These kids lose their vision and hearing; it’s a premature and accelerated degenerative process,” he says. “And although there is no cure, our work may lead to therapies for this and other neurodegenerative processes such as Alzheimer’s and Parkinson’s.”

Washington University in St. Louis will be the epicenter of the trial, though it will include Wolfram syndrome patients from all over the world, including France, Brazil, England, Spain, Italy and Jordan.

“This all comes down to funding,” Naseer says. “Clinical trials cost millions of dollars. It’s been tough, but our results keep coming back positive, and we have an overwhelming amount of interest in participating in this clinical trial. I think if we’re able to get a large donor, it would ensure that more patients are successfully treated in an expedited manner.”

 The Snow Foundation doesn’t have an office or salaries, so every single dollar goes directly to research.

“This is a David-and-Goliath kind of story,” Naseer says. “We’re small and underfunded, but I think with the right motivation and intention, we can go far in bettering the lives of these children.”

The Snow Foundation, P.O. Box 50224, Clayton, 636-448-4134, thesnowfoundation.org

 

Written By: Robyn Dexter

/by

Raquel and Braces

img_4753

Today Raquel is getting braces. It wasn’t the fear of her coming out with braces that heightened my anxiety, but it was the process. She was going to Demko Orthodontics, and they are wonderful. However, I was acutely aware of the fact that they probably have never had a patient like Raquel with some of her limitations.

I’ve been through the process of getting braces before with my two oldest daughters but it was different this time. We walked into our orthodontist office I said “go sign in sweetie.” But then I remembered, she can’t even see the computer to sign into. I have always raised my kids to be self-sufficient but Raquel is different. After I helped her sign in she was called back into the room. With my other daughters I would relax and do some light reading in the lobby but with Raquel’s hearing and vision loss, I sat there anxious as my mind ran wild.  What if the sharp tools scared her because she wasn’t able to see them until they were right next to her face? What if she panicked at the feeling of something drilling her teeth? I finally put my mind at ease by remembering I did the right thing by letting her go alone. I can’t coddle her forever.

I was hastily tapping my fingers against the chair armrest in the lobby when I saw Raquel walk into the lobby. I quickly jumped up to greet her. I got down on my knee and opened my arms to give her a tight hug. When I released, I looked at her and she was smiling. “How was it, sweetie?” I asked her.

Raquel then described to me a story that made my heart swell. Apparently, she daydreamed through the entire procedure and dreamt that she was flying. She touched the stars and when she woke up, she told the orthodontist that she flew. He told her that a superhero like her deserved a beautiful smile, and that he felt lucky he was able to give it to her.

Some days I struggle with feeling like the world is closing in on me, and that my daughter might never have the life that she deserves. Today, I felt lucky. Sometimes even the worst situations can have a positive outcome. Each day when Raquel faces changes in her life, I am afraid of what might happen. But today, when we come across people that help make it a little easier, it reminds me that my daughter is an inspiration. She has been dealt an unfortunate hand, but she remains strong and beautiful, and I can’t help but be proud of her.

/by

Finding A Cure for Victor

image

It’s been almost a year now since my 7 year-old son Victor was diagnosed with Wolfram Syndrome.  I still remember the day we found out, we got the diagnosis and then were basically sent home. Our doctor said all he could do is to try to treat the symptoms but not the cause because there was no treatment.  We live in Norway and to our knowledge there are only 3 other patients in the country with Wolfram syndrome. Our pediatrician had never heard of Wolfram Syndrome so he was not even able to provide further explanation or information to us.

At the moment our son only has 2 symptoms: diabetes mellitus and optical atrophy. We did not notice his vision loss until a routine check at school which diagnosed him with only 30% of his vision left. We sometimes still forget about Victor’s vision loss since he can still read, watch tv, and play tennis despite the optical atrophy.  It is difficult to think about how talented Victor is and not think about his future.  I spend nights wondering how long will he be able to live a normal life, how long will will be still be able to draw, how long will he still be able to hear the sounds of the birds in the morning, how long will be still be independent like other kids his age. The thoughts that rush through my head only bring me to tears.

My husband and I cannot simply live with the knowledge that our son will be suffering for the rest of his life and that he will probably die early without fighting; we need to stop this now! We are in 2016, we have found cures for many diseases and aggressive cancers. When will we find a cure for Wolfram syndrome?  We can and we must fix this so that when Victor eventually learns about his disease, he will see that he is not alone but that we have been fighting for a cure from day one. We are only defeated if we lose hope through all of this.

For the past 10 months, we have been looking worldwide to find a cure for our son.  The first experts who could tell us exactly what our son was suffering of were Dr. Urano and Dr. Barrett.  After speaking to them, we have a better understand of what we are dealing with. More importantly, they gave us hope. They are currently working on clinical trials for two drugs that can actually delay the progression of Wolfram. When we learned about their efforts and progress, we knew we needed to help find a cure for Wolfram Syndrome by raising money and creating awareness.

We have just started our first fundraising event and will soon provide our first donation to the ongoing Wolfram syndrome research efforts. Together with the other patient associations around the world, we want to join forces in order to beat this rare disease and save the lives of our precious children.

Please join us and the Snow Foundation to help find a cure for Victor and so many other children with Wolfram Syndrome.

– Eline Vanden Bussche

/1 Comment/by

How Do I Calm My Frantic Heart?

Judgment Day

No longer were the days of scheduled naps, gold stars, and lollipop rewards. For Raquel, no longer were the days of naive young children with innocent ignorance, but now the transition to very aware adolescents with a far too critical eye. I should have been excited at the idea of Raquel progressing in her life, but once she received her elementary graduate certificate, I was more afraid than ever.

It was the sixth grade orientation when my mind began to spiral. I was acutely aware of the way people looked at Raquel. The apprehensive looks and hesitant eyes were so apparent. A volunteer approached us and politely asked Raquel to sign her name without knowing that she couldn’t even see the place she was supposed to sign. It wasn’t her fault. It’s no one’s fault. However, that still did nothing for my peace of mind.

The Normal thing to do: A Wolfram’s fight

The long walk down the hallway filled with pre-pubescent eleven year olds was no better. Raquel’s older sisters were there to accompany her, but that still didn’t help when it came time for her to interact with the other children. After all, she couldn’t even see who was saying “hello” to her. How was she supposed to make friends, or fit in, when she can’t even distinguish one face from another? We all have an innate desire to be normal, and we usually easily achieve this, but Raquel is different. There’s always going to be the constant fight that comes with the realization that she will never be normal no matter how hard she tries.

The burden of Staples and Office Depot

From multi-colored notebooks to patterned binders and colorful backpacks, middle school transition should be fun and exciting. My eldest daughters had so much joy in picking out their bundles of school supplies at this same stage. This is where they got their first locker equipped with the too complicated combination for their ages. Raquel can’t have any of that. She doesn’t get a choice. She has to have supplies that help her see and a different lock on her locker because she is unable to use a regular lock. In the fight for normal, Raquel sticks out like a sore thumb.

Anxiety’s cure: Finding our blessings

We all take for granted what we have and how normal life is until you have to experience it first hand with someone who struggles each and every day of her life. As a parent, I can’t help but feel worried for my child and panic at each hour of the day just wondering if she is okay. The world can be cruel sometimes, and it kills me inside to know that I can’t always protect her. I do know, however, that I have to remain strong for my daughter. Each day she finds it within herself to fight for something normal. She has taken what life has thrown at her, and yet she continues to live, and for that I feel blessed.

/by

My Self Reflection by Federica D’Elia

federica-photo_o

It’s been about a year and a half since I was diagnosed with Wolfram syndrome. I look back and find myself self reflecting on my story and the emotional roller coaster that I have been though. When my doctors first gave me my diagnosis I felt strangely satisfied in some way. Until then, I had spent years in the unknown and plagued by symptoms that no one could give me an answer to. It was scary not knowing what was wrong with my body and also upset no one could tell me what was going on. I just kept hearing my doctors tell me ‘they are looking into it’ and ‘sorry we don’t have the answers’ but finally after years of unexplained symptoms, I finally had the answer I needed.

However it wasn’t long before a new wave of emotions came over me..  I first became angry that it had taken so long for them to find out I had Wolfram syndrome. Wolfram isn’t a disease with slow progression, so I felt I had lost a lot of valuable time not knowing how to fight this or knowing how to take my of myself in the best way possible. After I calmed down I began to feel alone and fearful. Since Wolfram syndrome is rare disease it only affects a small percentage of the population, I began to worry I would have a hard time finding a support group that would understand what I was going through.

Thankfully after days and months of research I found online support groups for Wolfram patients. My mind was finally at ease knowing I was no longer alone in this journey.  I feel so blessed to meet and talk to others like myself and hear their stories and my self esteem has recovered and grown through these amazing groups and individuals.

Today, thanks to myself, my family and other great supportive people in my life I have risen above my original emotions and now hold my head up high with a drive. Since being diagnosed with Wolfram syndrome my vision of life has changed. As Wolfram syndrome is a rare disease, I now know that I need to bring awareness of this awful disease. I didn’t want others to spend years alone with no diagnosis wondering what was wrong with them and why no one could give them answers. I want to make sure that they have all the resources they need to fight Wolfram syndrome as early has possible.

Although I have been through many difficulties in my life, I have also had so many amazing opportunities. I could have spent my life focused on all the negative aspects and been alone and at the bottom of a whole but I choose to look at the positive side of this. Once you hit rock bottom you can only go up from there. I have chosen to hold my head up high, climb up and help others up as well!

– Federica D’Elia

/by

A neurodegenerative perspective on mitochondrial optic neuropathies

Publication: www.ncbi.nlm.nih.gov | Publication Date: September 30, 2016

Authors: Patrick Yu-Wai-Man, Marcela Votruba, Florence Burté, Chiara La Morgia, Piero Barboni, and Valerio Carelli

Abstract

Mitochondrial optic neuropathies constitute an important cause of chronic visual morbidity and registrable blindness in both the paediatric and adult population. It is a genetically heterogeneous group of disorders caused by both mitochondrial DNA (mtDNA) mutations and a growing list of nuclear genetic defects that invariably affect a critical component of the mitochondrial machinery. The two classical paradigms are Leber hereditary optic neuropathy (LHON), which is a primary mtDNA disorder, and autosomal dominant optic atrophy (DOA) secondary to pathogenic mutations within the nuclear gene OPA1 that encodes for a mitochondrial inner membrane protein. The defining neuropathological feature is the preferential loss of retinal ganglion cells (RGCs) within the inner retina but, rather strikingly, the smaller calibre RGCs that constitute the papillomacular bundle are particularly vulnerable, whereas melanopsin-containing RGCs are relatively spared. Although the majority of patients with LHON and DOA will present with isolated optic nerve involvement, some individuals will also develop additional neurological complications pointing towards a greater vulnerability of the central nervous system (CNS) in susceptible mutation carriers. These so-called “plus” phenotypes are mechanistically important as they put the loss of RGCs within the broader perspective of neuronal loss and mitochondrial dysfunction, highlighting common pathways that could be modulated to halt progressive neurodegeneration in other related CNS disorders. The management of patients with mitochondrial optic neuropathies still remains largely supportive, but the development of effective disease-modifying treatments is now within tantalising reach helped by major advances in drug discovery and delivery, and targeted genetic manipulation.

Read the entire publication article here.

/by

3 Things on my Mind When I Work on Wolfram syndrome

While working on Wolfram syndrome there are three things that are always on my mind: improving clinical care, raising awareness, and providing a cure. These three things motivate myself and my team to work hard every day.

 

Improving Clinical Care

Our effort to understand the progression and neurological symptoms of Wolfram syndrome will help improve the clinical care we give our patients. Clinical trials throughout the world have specific qualifications before they begin and thanks to our researchers from around the globe in the last few years there has been significant progress and we now know the appropriate measurements to use in our clinical trials. There are also new hypotheses on how Wolfram syndrome affects the brain that will soon be tested in research models, which will lead to more targeted treatments for the neurological systems and improve the clinical care for the patients. This is all thanks to multiple foundations around the world like The Snow Foundation who are helping us raise awareness and helping us raise funds to make these trials possible.

 

Raising Awareness

Awareness for Wolfram syndrome has grown significantly with help from advocate groups such as The Snow Foundation and the Ellie White Foundation. We could not have accomplished the research we have conducted so far without these organizations and other advocate groups  and we want to thank and recognize all the groups for being a part of our research efforts. However we still depend heavily on NIH (National Institutes of Health) grants to help us with a significant amount of funds for our research to find a cure. NIH grants have increasingly difficult to get and we are working on getting more funding in the next year. The awareness and research funds play the largest part in helping us find a cure for Wolfram syndrome.

 

Providing a Cure

To provide a cure, we need to first delay the progression of the disease so that we have more time to develop regenerative therapies and gene therapies. To accomplish this milestone, I have been focusing on “repurposing” one of the FDA-approved drugs (i.e. existing drugs) for the treatment of patients with Wolfram syndrome.  We have been making steady progress on this.

As I reported before, we discovered that dantrolene sodium currently approved for the treatment of spasticity (muscle stiffness) could delay the progression of Wolfram syndrome in animal and cell models. We obtained the orphan drug designation of dantrolene sodium for the treatment of Wolfram syndrome from the US FDA early in 2016.

I have been working on the logistics to commence a clinical trial of dantrolene sodium for the treatment of Wolfram syndrome at our medical center. I hope to start the trial in December of this year and the plan is to enroll 25 patients or more. The trial may last 2 years. I plan to monitor safety, vision, neurological functions, and diabetes in our patients since those are the primary indicators of Wolfram syndrome. As I reported before, type 2 diabetes is associated with Wolfram syndrome 1 gene variations.

We are trying to get more funds from the National Institutes of Health to recruit more patients, and we want to thank The Snow Foundation and Ellie White Foundation for planning to support this trial financially.

/by