COLUMBUS, OH ( Ivanhoe Newswire) - It attacks the heart and breathing muscles in boys and young men. Those with Duchenne Muscular Dystrophy will likely die well before they reach their mid-20s. Now, one young man and his father are focusing on prolonging lives until there's a cure.
Ryan Ballou suffers from a rare genetic disease passed from mother to son. It causes breathing and heart muscles to breakdown and fibrosis or scarring to develop. Ryan's dad Ty knows it will eventually kill his boy.
"Ryan will have lung failure and or he will have a heart attack," Ty Ballou told Ivanhoe.
But because of various medications, Ryan's damaged heart is still strong. Cardiologist Subha Ramen saw promise in the minimally scarred muscle.
"So, it made me wonder if it was possible to treat fibrosis at an early stage," Subha Raman. M.D., a professor of cardiovascular medicine at the Ohio State University Medical Center, told Iexplained.
Along with Ohio State University, researchers Jill Rafael-Fortney and Paul Jansen, Dr. Ramen wanted to test a combination of the common heart failure drugs-spironolactone and Lisinopril.
"Both of the drugs are known to be anti-fibrotic or prevent scarring," Rafael-Fortney,M.D., an associate professor of molecular and cellular Biochemistry, at the Ohio State University, said.
But there was no money to do that, so, Ty and Ryan created Ballou Skies.
"I said to hell with it. Whatever you need, you get the kids, we're gonna get the money. I started doing these crazy triathlons," Ty said.
Now, Ballou Skies has its own triathlon team. Ty said with help from the athletes Ballou Skies has raised more than $70,000 for the research effort.
"It's nice that we're actually kind of helping speed along the research," Ryan said.
Wearing a Ballou Skies bracelet for inspiration, Dr. Ramen said without that money there would be no research. Now that it is happening the team is seeing improvement in heart muscle structure and function. And they're surprised by the effects on skeletal muscles.
"We saw a doubling of muscle force, so the muscles in the limb and the diaphragm were twice as strong," Dr.Fortney said.
Results made possible by Ballou Skies that could someday prolong its co-founders life and others just like him. Clinical trials are expected to start in the next several months. Doctor Ramen said because both drugs are already available the FDA can use data from the clinical trials to add MD treatment to their existing approved uses. Ty says he needs to raise more than $200,000 to help fund the work. If you'd like to donate to the cause go to ballouskies.com.
BACKGROUND: Duchenne Muscular Dystrophy, DMD, is an inherited disorder that involves rapidly worsening muscle weakness. It is one of nine types of muscular dystrophy. Men are more likely than women to develop symptoms of the disease; approximately one out of every 3,600 male infants develops the disease. (SOURCE: www.ncbi.nlm.nih.gov)
CAUSES: It is caused by a defective gene for dystrophin, a protein in the muscles.
SYMPTOMS: Symptoms of DMD can include fatigue, mental retardation, muscle weakness that begins in the legs and pelvis area causing frequent falls. Also, progressive difficulty walking is a sign of DMD. (www.ncbi.nlm.nih.gov)
COMPLICATIONS: There are a series of complications related to DMD. Complications can include heart disease, congestive heart failure, deformities, heart arrthymias, mental impairment, pneumonia or other respiratory infections and also respiratory failure. (www.ncbi.nlm.nih.gov)
TREATMENT: The two drugs Spironolactone and Lisinopril are used for other forms of heart disease. The combination of the two is being studied for the treatment of DMD due to the disease causing breathing and heart muscles to breakdown and fibrosis or scarring to develop.
For the study, the drugs were tested on mice. One group received both drugs at eight weeks of life; the second group at four weeks and the third group received no treatment. At 20 weeks all mice had a normal amount of blood pumped through the heart from the right and left ventricles with each heartbeat.The treated mice showed less heart muscle tissue damage. In general, it is suggested that individuals with DMD stay active, such as through physical therapy which can help maintain muscle strength and function. Inactivity can worsen the muscle disease. (SOURCE : Circulation: The Journal of the American Heart Association; www.ncbi.nlm.nih.gov)
Jill Rafael-Fortney, Ph.D., Associate Professor in the Department of Molecular and Cellular Biochemistry tells us about a new study Muscular Dystrophy.
Tell us the work you're doing and how long you've been working on this study.
Dr. Rafael-Fortney: This particular study took about a year, the initial study, and we're continuing to work on it. I've been working in the field of Muscular Dystrophy for my whole career. This study initiated in April of 2010.
Why did it start?
Dr. Rafael-Fortney: Subha Raman spurred the idea since she is a cardiologist who sees the adult Duchenne Muscular Dystrophy patients and Becker Muscular Dystrophy patients. She and others had been noticing and publishing that the cardiac damage in Muscular Dystrophy occurs years before the heart starts to lose function. So she was starting to put patients on the standard of care heart failure medications as soon as she saw damage. And in a small handful of patients it seemed to be preventing further damage. So she came to us and said, you have the right mouse model so let's do a real experiment to see whether we can prevent damage before it starts in the mouse model of Muscular Dystrophy. I then looked in to the drugs she was talking about putting patients on, which were Lisinopril,an inhibitor of the angiotensin converting enzyme that's a standard of care heart failure drug. And then a drug called spironolactone which is usually used later and closer to end stage heart failure. And both of those drugs are known to be anti fibrotic or prevent scarring. And the major problem in both the skeletal muscle weakness in Muscular Dystrophy and the heart failure is a breakdown of muscle tissue and build up of scarring. So I thought well if we're looking for drugs that are anti fibrotic why don't we see if they can prevent scarring in skeletal muscle as well. And so with the help of Paul Jansen who is a muscle physiologist we were able to do a really comprehensive study of heart, limb muscle and one of the most important muscles diaphragm, which is the muscle you need to breathe properly. The majority of patients still die of respiratory failure because the diaphragm becomes a big scar instead of a muscle. My lab has the model and we did all of the histological analysis to be able to look at how healthy the muscles were and Paul's lab right next door was able to measure the strength of each of the muscles. Then Subha Raman's lab analyzedmagnetic resonance imaging, MRI, on the mice just like she does on patients so we were able to do the comparison of whole heart function as well.
You put them on a combo of these drugs, what did you see when you did this?
Dr. Rafael-Fortney: Our thought was that the drugs would have an improvement on heart histology and heart function and we did indeed see that. What was surprising was when we looked at skeletal muscle and we were maybe hoping for a minor affect on scarring we saw a doubling of muscle force. So the muscles in the limb and the diaphragm were twice as strong as in the Muscular Dystrophy animals. And that amount was eighty percent of normal muscle function. They went from forty percent to eighty percent with treatments of the drugs.
When you saw that how excited were you?
Dr. Rafael-Fortney: It was unbelievable and so at the histological level we saw the damage when we started treatment early enough in skeletal limb muscle was almost completely prevented. So there was a little bit of damage that happened early but once we started the drugs there was no current ongoing muscle breakdown anymore and less scarring. We were seeing the effects on two different parameters and it was fairly obvious that we were seeing something dramatic and real because we had so many different types of information about the disease process.
Does the combo halt that deterioration or does it actually reverse it?
Dr. Rafael-Fortney: We haven't directly assessed whether it reverses any of the pathology but we had an earlier treatment group and a slightly later treatment group further in to the cardiac and the muscle pathology and earlier treatment is better. And I think that's really the paradigm of what's happening in all genetic diseases that are progressive is that earlier treatment is always going to be better. Preventing damage is always easier than trying to reverse damage that's already there. Once a cell has died it's died and it's really hard to replace that.
This is kind of still in the animal model phase but at the same time there is someone who has been on this.
Dr. Rafael-Fortney: So Spironolactone has been used in addition to Lisinopril on DMD patients and Becker patients once they already have shown heart problems, the initial stages of heart failure. Some of the cardiologists since hearing this have started putting all of their patients on Spironolactone at the same time that they start them on Lisinopril. Spironolactone has not yet started to be used preventatively and we're planning clinical trials in collaboration with Nationwide Childrens Hospital to look at the skeletal muscle prevention which happens much earlier than the heart disease. And Subha Raman is planning clinical trials to look at the prevention of heart failure. But they will happen in two separate trials because patients are wheelchair bound prior to really getting serious problems with the heart failure. So we're talking about treating patients for the skeletal muscle problem at about five years of age when they can accurately be measured for muscle testing and then older children, early teenagers for the heart failure trial.
Let's talk about MD actually is and what it does to the body.
Dr. Rafael-Fortney: Duchenne Muscular Dystrophy is a disease that only affects boys. It's on the X chromosome and you inherit it from your mother. It is a muscular degenerative disease. So all the skeletal muscles in the body including the muscles you need for respiration like your diaphragmdegenerate and become replaced by connective tissue scars so muscles become more and more nonfunctional because you're replacing muscle with scar. And the heart is also a similar type of muscle, a striated muscle, which undergoes the same pathway of degeneration and scarring until it also becomes nonfunctional. Currently about two thirds of patients die from respiratory failure and about a third die from heart failure and as some prophylactic treatments to keep respiration up improve, more patients will die of heart failure. So we had initially started focusing on the heart failure but we found a drug that works on all the types of muscles.
Is there a life expectancy?
Dr. Rafael-Fortney: The current life expectancy over the past few years has crept up in to the early twenties. It used to be fatal in the teens but due to basically prophylactic antibiotic treatment so that patients don't get respiratory infections when their muscles can no longer clear their lungs and better ventilatory support many patients are surviving into their early twenties. It's still considered a childhood fatal disease. It's a horrible disease--patients are wheelchair bound by the ages of eight to eleven and are usually on some sort of respiratory support and cardiac care by their early teens.
When do you think this treatment will be the norm for helping prevent?
Dr. Rafael-Fortney: It's never going to be a cure because it's not going to completely replace the protein that's missing in patients which is the dystrophin protein. There are a lot of labs working trying to put dystrophin back in and trying to up regulate a compensatory protein called utrophin. But right now the only standard of care is prednisone or deflazacort, glucocorticoids which have a litany of severe side affects. Their result right now is to delay the progression of being wheelchair bound by two to three years in most cases. So getting a pharmacological FDA approved drug treatment that would have at least that affect without the horrible side-effects of long term steroid use I think would quickly get to patients as soon as there is a small clinical trial held that shows efficacy in patients.
So these are things that are already on the market.
Dr. Rafael-Fortney: For years, they're both off of patent actually. Spironolactone has been around for about eighty years. It has so few side-effects that your GP tends to prescribe it for unwanted facial hair in women. So these are drugs that have so few side-effects and are already in use in the pediatric population. Spironolactone is given to babies that are born with congenital heart problems so it's safe and effective in pediatric patients with other diseases.
So you have to have that FDA approval to have them work as a combo?
Dr. Rafael-Fortney: It will probably be an FDA exemption we will probably not have to go through the whole approval process. The plan is to put in a request for exemption.
Is there a time line, are you looking for next year?
Dr. Rafael-Fortney: As soon as the trials can be funded. There's some cost to them. A lot of the assessment will be done under standard of care the patients are getting and are routinely assessed anyway. But the cost of the drugs which is fairly low because they are off patent and funding for travel to the centers that we'll be able to conduct the clinical trial. The clinicians who will be running the trial are trying to get the funding right now.
So there's no cure but this helps extend lives and improve quality of life?
Dr. Rafael-Fortney: Right, it could have a huge improvement if we see the same results in patients that we saw in this first study in the mice. I think eighty percent of normal function you'd be able to lead a relatively normal life. I think by the time most of us are in our forties we're down to eighty percent of normal function. Maybe the patients won't be marathon runners but they might be able to really live normal lives and have normal jobs and go about their daily lives for a lot longer. We still have major questions to ask in the mice that we're doing now and how long does the effect last. We've only done it for a relatively short period of time and other drug studies that haven't looked quite as dramatic but had some effect at young ages didn't last. As the case with the current standard of care with the prednisone, there's a two to three year window and then the decline parallels untreated patients.
Does the therapy get rid of that scarring and then allow muscle to grow back?
Dr. Rafael-Fortney: We have not defined the whole mechanism because this is all still very new and we're working on it but the current data which was in the original paper is that we think it's somehow preventing the muscle from dying. That it's not actually working at the level of preventing the scarring that it's working upstream from that. And so even though the drugs have been thought of as anti-fibrotic the result is you don't get scarring or fibrosis. But we don't think it's actually working that far down the pathway. We think it's happening by preventing the muscle cells from dying. We just see very, very little damage in the early treated mice in heart and skeletal muscle.
So you would diagnose a patient when he was a toddler and then you would start the therapy thus preventing?
Dr. Rafael-Fortney: That would be the hope is that you could halt the damage for a long period of time as soon as the diagnosis was made. I mean if there is an effective treatment it would also argue for neonatal diagnosis. Because it is possible it's just that without really good therapies around there's a cost benefit analysis to insurance companies that it's not worth doing the screening if you can't do anything about changing the course of the disease. If there was a therapy that could change the course of the disease you could do screening in the hospital for newborns just like PKU and other diseases that are routinely screened for.
So you would know whether they had Muscular Dystrophy when they are born?
Dr. Rafael-Fortney: Right, it's a genetic disease so you can diagnose it right at birth.
It sounds like a personal battle for you.
Dr. Rafael-Fortney: Watching the Muscular Dystrophy Association Jerry Lewis Labor Day Telethon when I was a little girl really changed the course of my life. It motivated me to help kids who were just like me but they weren't able to live the same life that I was and do all the things that I could. And so at the age of six all I could do was save up my allowance but as I got older I figured out that research was the way that I thought I could best help. And I did my Ph.D. working on Muscular Dystrophy and understanding how the dystrophin protein worked, the protein that's missing in Duchenne Muscular Dystrophy. And then I did a post-doctoral fellowship at Oxford to keep working on the disease and then I started my own lab here because OSU is a rare place where physicians and scientists can work together to really ask the important questions to improve the lives of patients with muscular dystrophy.
FOR MORE INFORMATION, PLEASE CONTACT:
Marti Leitch Senior Manager, Public Affairs & Media Relations Ohio State University Medical Center (614) 293-3737 email@example.com
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