Author and Contributing Experts to this Guide include:
What is Duchenne Muscular Dystrophy?
Duchenne muscular dystrophy (DMD) is the most common childhood onset form of muscular dystrophy 1. It is a genetic disorder characterized by a harmful change in a gene called DMD. This gene is responsible for making a protein called dystrophin which works to keep muscle cells together. Conditions that affect dystrophin, like DMD, are called dystrophinopathies. Other dystrophinopathies include:
- Becker Muscular dystrophy (BMD) which is a mild form of DMD
- An intermediate clinical presentation between DMD and BMD
- DMD-associated heart-disease referred to as dilated cardiomyopathy. It has little or no clinical skeletal, or voluntary, muscle disease.
When dystrophin is not working correctly, an individual can experience muscle weakness, delay in motor development, loss of muscle mass, cardiac complications, and respiratory complications. Symptoms of DMD usually first appear in early childhood, between 2 and 3 years old. It primarily affects boys, but in rare cases, it can also affect girls.
DMD was first described by French neurologist Guillaume Benjamin Amand Duchenne in the 1860s 2. However, it wasn’t until the 1980s when MDA-supported researchers identified the causative gene on the X chromosome 3.
Duchenne vs Becker Muscular Dystrophy
While this guide focuses primarily on Duchenne muscular dystrophy, it is important to note that it is closely related to Becker muscular dystrophy. Both conditions are due to harmful changes in the DMD gene, but the severity of symptoms differs between the two.
“Duchenne and Becker muscular dystrophy are actually both caused by mutations in the dystrophin gene. If the mutation results in no dystrophin protein being produced, then usually the boy will have Duchenne, whereas if the mutation allows for some dystrophin protein production, then usually the boy will have a milder Becker presentation,” explained Ann Martin, a genetic counselor and Director of the Duchenne Registry at Parent Project Muscular Dystrophy.
Duchenne and Becker muscular dystrophies differ in their severity, age of onset, and rate of progression.
“It’s really easier to think of these diseases on the same spectrum, with Becker being at the milder end of the spectrum, and Duchenne being at the more severe end of the spectrum,” she added.
Boys with DMD will see muscle weakness in early childhood that will rapidly worsen, causing delays in motor skills such as sitting, standing and walking. Boys with DMD are usually wheelchair-dependent by adolescence 4.
Becker muscular dystrophy is usually milder and more varied. In most cases, muscle weakness becomes apparent later in childhood or in adolescence and worsens at a much slower rate.
Both the Duchenne and Becker muscular dystrophy are associated with a heart condition called cardiomyopathy. This indicates that the muscles of the heart are weaker than they should be and therefore have difficulty pumping blood throughout the body 5. In both DMD and BMD, cardiomyopathy can appear in adolescence with a diagnosis occurring on average at 14 years 6.
After awhile, the heart will grow larger than normal (dilated cardiomyopathy) and this can lead to the having an irregular heartbeat (arrhythmia), the patient feeling short of breath or extremely tired, and swelling in the legs and feet. For individuals with DMD, approximately one third of individuals will have cardiomyopathy by 14 years, half by 18 years, and all will be affected after 18 years 7.
Most patients with DMD live past their 30s. Most patients pass away from respiratory complications and cardiomyopathy 8 9. However, new developments in treatment and management are looking to increase life expectancy. While there is no known cure for DMD, there are treatments that can help control symptoms.
What Parts of the Body Does Duchenne Muscular Dystrophy Affect?
Individuals with DMD will experience weakness in proximal muscles this is to say their arms and legs. Signs and symptoms of weakness are often present in individuals before 5 years of age.
This can lead to a child having difficulty jumping, climbing stairs, maintaining balance, running, and walking. However, individuals with DMD will eventually reach these milestones. When the first begin to stand-up they might have to support their bodies by placing their hands on their knees and walking their hands up until they are standing (Growler’s maneuver).
In addition to the skeletal muscle weakness, the majority of patients with DMD will also experience cardiomyopathy. This will not initially cause any signs or symptoms, but overtime can lead to differences in the way the heart beats 12.
In males with DMD, there is evidence of cognitive impairment. In general the IQ of individuals with DMD tends to be slightly lower than that of the general population.
Some individuals might have intellectual disability while others might have a learning disability, attention-deficit hyperactivity disorder (ADHD), anxiety, or autism spectrum disorder 13.
What Causes DMD?
Individuals with Duchenne muscular dystrophy have genetic differences in their DMD gene that causes the dystrophin protein to not be produced. This is often due to a deletion or duplication of information inside of the DMD gene 14. Different changes within the DMD gene can lead to milder signs and symptoms which correspond with a diagnosis of Becker muscular dystrophy.
“Duchenne is caused by mutations or changes within the dystrophin gene which makes the dystrophin protein, and the dystrophin protein plays a critical role in the stability of the muscle cell membrane. So, without dystrophin the muscle cells can easily degrade and this leads to the progressive muscle weakness and wasting that we see in Duchenne,” said Martin.
The DMD gene lives on the X chromosome which is one of our sex chromosomes. Females have two copies of the X chromosome.
Therefore, if one of their X chromosomes is carrying a non-working copy of DMD, they have a backup working copy on the other X chromosome. However, males only have one X chromosome, so if their copy of DMD is not functioning the way it should then there is not a backup copy.
This is why males are more likely than females to have Duchenne Muscular Dystrophy.
Because the DMD gene is located on the X chromosome it is said to be inherited in an X-linked inheritance pattern. If a female, with a non-working copy of DMD has a son, then there is a 50% chance that he will have Duchenne muscular dystrophy.
Her daughters would have a 50% chance of also carrying the non-working copy of DMD. If a father with DMD has children, then there is a 100% chance that all of his daughters will be carriers, and a 0% chance that his sons will be affected. This is because the father can only pass the Y chromosome onto his sons.
In two-thirds of cases, the mother of a son with DMD will be a carrier. However, in one-third of cases, the genetic change that causes the DMD gene to not function appropriately will occur for the very first time in the son. When this occurs, we say that the genetic changes occurred de novo.
“About 30 percent of boys who are diagnosed with Duchenne have what we call ‘de novo’ or a spontaneous gene change that occurs for the first time in them. They are the first person in their family to be affected. The other 70 percent of boys who are diagnosed with Duchenne inherit the gene mutation from their carrier mother, but she may not have known she was a carrier until she had an affected child,” added Martin.
“Even if we could identify every carrier mother and provide genetic counseling before she becomes pregnant, there are still going to be a large number of cases that occur just spontaneously,” added Martin.
Most of the time, female carriers will not experience the muscle weakness or cognitive differences seen in affected males. However, females can develop the same classical features that are seen in males although it is rare 15 16. These females are considered to be manifesting carriers. Sometimes, female carriers can experience cardiac issues, and therefore it is important that female carriers undergo a cardiac evaluation.
“More and more women without any family history of Duchenne are finding out that they're carriers because Duchenne has been added to many of the universal carrier screens that are now offered to pregnant women or women who are considering pregnancy,” said Martin.
Prevalence and Risk Factors for Duchenne Muscular Dystrophy
According to Martin, “Duchenne affects about one out of every 5,000 live male births. It can affect any race.”
Between 400 and 600 boys in the United States are born with Duchenne or Becker muscular dystrophy each year.
“Worldwide, the rate of incidents are similar. Life expectancy will vary from country to country depending on standards of care and just access to medical care. As the boys get older into their teens there begins to be a noticeable decline in pulmonary and cardiac function, not just the skeletal muscle strength and the skeletal muscle function.
“So, it's very important to recognize those issues early on and treat as preemptively as you can with the various medications and respiratory modalities,” said Dr. Edward Smith, a pediatric neurologist at Duke University Hospital who specializes in neuromuscular disorders.
Signs and Symptoms of DMD
There are several signs and symptoms that suggest a person has Duchenne Muscular Dystrophy. In a vast majority of cases, the following signs and symptoms are common in males, but females may also be affected as well.
“Duchenne is characterized by progressive loss of muscle and this results in deterioration of not only the skeletal muscle but also the heart and the lung muscles. Most boys with Duchenne will need to use a wheelchair for mobility by, on average, 12 years of age, and many will die in their teens or 20s from cardiac or respiratory failure,” said Martin.
Specific signs and symptoms of each dystrophinopathy include:
Duchenne Muscular Dystrophy 17:
- Progressive symmetric muscle weakness
- Symptoms present before age five years
- Wheelchair dependency before age 13 years
- Using hands to get up off the floor (Gower's maneuver)
- Scoliosis and tight joints (contractures) may develop as muscle loss progresses.
- General motor delays and gait problems including persistent toe-walking and flat-footedness
- Learning difficulties and speech problems, attention-deficit hyperactivity disorder (ADHD)
- Calf muscles that are hypertrophic and firm to palpation, occasionally there is calf pain
- Reduced mobility resulting in decreased bone density and an increased risk for fractures. Corticosteroids further increases the risk of vertebral compression fractures, many of which are asymptomatic.
- Generalized hypotonia
“It's really important to point out that Duchenne isn't just a disease of the muscles, it actually affects almost every system in the body, and for this reason we do recommend that all individuals with Duchenne or Becker be followed at a multi-disciplinary clinic that specializes in Duchenne,” explained Martin.
The Progression of DMD
18DMD is a progressive disease meaning the body’s muscles will continue to weaken over time. Unfortunately, once the muscle tissue has weakened it is unable to be fixed. Signs and symptoms of DMD will start to become noticeable in early childhood.
As an individual grows and develops new signs and symptoms will become apparent. It is important to remember that no individual with DMD is exactly the same. The exact progression will differ from person to person.
Parent Project Muscular Dystrophy has outlined five general stages of progression 19:
- Diagnosis. Diagnosis of DMD typically occurs in infancy or early childhood. Parents tend to notice that their child is not meeting the typical developmental milestones and might bring this up to their primary care physician.
- Early Ambulatory Phase. This lasts until around age 7. Typically, there are not many signs and symptoms of DMD at this phase. Individuals might have difficulty engaging in motor activities such as climbing stairs or running with their friends. It is during this period that certain interventions, such as steroids, might be started.
- Late Ambulatory Phase. During this phase, fatigue and difficulty walking for long periods of time will become noticeable. It might be helpful to start using a scooter or wheelchair for long distances. Additionally, other management recommendations will become important such as monitoring breathing, heart, and bone health.
- Early Non-Ambulatory Phase. During this phase, individuals will see a big impact on their independence as they become more reliant on a wheelchair. Legs and arms will continue to weaken. Most children with DMD do retain use of their hands and fingers, so children can continue to use a computer in many cases. Scoliosis becomes more pronounced, and heart and breathing function will become more challenging during this phase as well. It is important that patients receive regular care from their medical team.
- Late Non-Ambulatory Phase. During this phase, the focus is ensuring that patients are receiving regular care in order to maintain their independence. Medications are often necessary to alleviate symptoms and breathing support through the use of a ventilator is common.
Potential Complications from DMD
There are complications that arise as DMD produces progressive muscle weakness. Those complications include:
Breathing problems. Muscles associated with breathing are weakened to the point where people with DMD may need to use a breathing ventilator. Initially, a ventilator may only be required at night, but eventually round-the-clock use could be required.
Scoliosis. 20 Weakened muscles may not be able to keep a person’s spine straight.
Heart problems. 21 DMD can have a severe impact on the heart, reducing its efficiency significantly. Eventually this could lead to heart failure.
Mobility issues. People with DMD eventually need to use a wheelchair to assist them with mobility. Frequent falls can put someone with DMD at constant risk.
Trouble using arms. DMD affects arms and shoulders, making several daily tasks much more challenging. Contractures in muscles or tendons around joints can have a profound impact on mobility.
Swallowing issues. When the muscles that involve swallowing are affected, this can create nutritional problems. Aspirational pneumonia may also develop. Often, this is remedied by the use of a feeding tube.
Neurological Conditions. 22 DMD patients often have neurological disorders, including epilepsy, which can lead to seizures. Other similar issues may result in ADHD, obsessive-compulsive disorder, anxiety or sleep disorders.
Diagnosis of Duchenne Muscular Dystrophy
“Boys are typically diagnosed between three to five years of age, but this can really vary considerably in the US and even worldwide. They usually present with trouble running or climbing stairs. They often have frequent falls. They can have enlarged calf muscles and sometimes even language delays in addition to the gross motor issues,” according to Martin.
DMD is diagnosed by evaluating numerous areas including: family history, a clinical examination, signs and symptoms, and genetic testing. Blood tests are administered to check for increased levels of muscle enzymes that are used to check for muscle damage.
“The first test a doctor will usually order when he or she suspects muscular dystrophy is a blood test for creatine kinase or CK, and this is a marker of muscle cell degradation.
“Boys with Duchenne and Becker have extremely elevated serum CK values. And then if the CK is elevated usually the doctor will order genetic testing to confirm the diagnosis of Duchenne or Becker,” said Martin.
“In addition to the CK and the DNA test, sometimes doctors will order a muscle biopsy to actually determine exactly how much dystrophin is present in the muscles. But with molecular technologies being so advanced today, muscle biopsies are no longer routine and are performed much less often than they used to be.”
Genetic testing can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing.
Single gene testing is performed first because the majority of individuals with DMD have a deletion in the DMD gene. If a deletion or a duplication is not seen, then the laboratory will then look at the sequence and see if there are any harmful changes.
A multigene panel is often ordered when physicians are not sure of the exact condition. They will therefore order a panel that includes a number of genes that can be associated with the signs and symptoms of the patient. The panel will include the DMD gene and therefore can diagnose Duchenne Muscular Dystrophy.
Sometimes patients with DMD, might undergo a larger test such as an exome or genome. Sometimes this test picks up patients who might not share the typical features of DMD.
There are several options for prenatal testing. People with a family history of Duchenne or Becker who have been identified as a carrier can have standard prenatal diagnostic procedures done.
“These include either chorionic villi sampling or CVS. That's done at the end of the first trimester, or amniocentesis in the second trimester. And both of these are truly diagnostic tests so they would tell you whether or not your baby inherited the Duchenne gene mutation,” said Martin.
Women who are carriers can actually prevent the conception of an affected child through a technique called pre-implantation genetic diagnosis. In vitro fertilization is first performed using the mother's egg cells and her partner's sperm cells, and then the embryos are tested for the Duchenne mutation. Only the unaffected embryos are implanted back into the mother's uterus.
This technique is well established and has been done for many years at several centers across the United States.
Treatment & Care Options for Duchenne Muscular Dystrophy
Although significant research and clinical trials are being conducted, there is no known cure for DMD.
Treatment involves an integrated approach using a team of specialists that may include:
- Pulmonologist (lung specialist)
- Genetics specialist
- Physical therapist
- Occupational therapist
“Care guidelines were developed by the Centers for Disease Control, in tandem with a large patient advocacy group called Parent Project Muscular Dystrophy, or PPMD. The first version of those were published I believe it was 2009, and then were updated recently, a little over a year ago.
“That's a great start because that document lays out what good Duchenne care should look like. Not all clinics are able to offer all of that, especially not in a coordinated fashion, but there are some key team members so any child or adult with Duchenne should have access to certain specialists,” said Dr. Smith.
After an initial diagnosis, or even when it is suspected, a neurologist is often the first specialist that should be engaged.
“Ideally a neuromuscular neurologist should be the initial contact, but there are very few of those in the country, so sometimes a Duchenne clinic might not be run by a neurologist. It might be run by a pediatric cardiologist, or even a pulmonologist, or a physical medicine and rehabilitation doctor.
“It doesn't have to be a neurologist, but you need someone who understands what Duchenne muscular dystrophy is and understands the need for multidisciplinary care, whether it's truly coordinated care or just separate visits to separate doctors,” added Dr. Smith.
In general, administering steroids may improve the strength and function of muscles. Depending on the specific genetic difference in the DMD gene, some individuals might have additional medications available to them 23.
In cardiology care, patients are usually offered ACE inhibitors and Beta-blockers to help with an enlarged, weakened heart, but if there is severe damage, a heart transplant may be necessary.
The Food and Drug Administration (FDA) has approved some medications to treat DMD. They include 24:
Deflazacort (Brand name: Emflaza) - Manufactured by PTC Therapeutics with an FDA-approved indication in February 2017, it was approved to treat DMD in patients 5 years and older.
Eteplirsen (Brand name: Exondys 51) - Manufactured by Sarepta Therapeutics, Inc. with an FDA-approved indication in September 2016. This drug was approved for DMD patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping.
Golodirsen (Brand name: Vyondys 53) - Manufactured by Sarepta Therapeutics, Inc. with an FDA-approved indication in December 2019, this drug was approved to treat DMD in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping.
Ongoing physical therapy is critical to promote mobility and prevent contractures.
“We realized that drug development takes a long time and that we needed to do something to take care of the kids while we were developing these drugs, so we started the CureDuchenne program,” said CureDuchenne CEO Debra Miller.
“It has grown into just an incredible resource where the pioneers are basically taking best care practices on the road to the patients and their communities because there just weren't that many physicians who really understood how to treat patients with Duchenne.
“This was especially true for physical therapists, because there are some nuances to treating Duchenne patients that a lot of physical therapists did not know, and you can actually do some harm instead of good,” added Miller.
Attending to nutritional issues is also a critical component of treatment.
“The standard of care therapy for all boys with Duchenne, is corticosteroids, glucocorticoids like prednisone or another one called deflazacort. All of those come with a lot of side effects, in particular weight gain, but also weakening of the bones and short stature among many other things,” commented Dr. Smith.
Weight gain is a tremendous issue and is largely related to the steroids in many of the boys. Steroids are used as treatment because they have been shown to slow progression a little bit.
“It slows the progression and delays the age at loss of walking ability by a couple of years, so the boys still head in that direction but just more slowly. It also slows progression of weakness in the upper extremities, the arms and the hands as well.
“Steroids come with huge side effects, and weight gain is part of that. A nutritionist or dietician in clinic is a very important source of information for families. Increased weight requires more effort to move around, and if your muscles are weak or getting weaker, that can impact your ability to function.
“The steroids also can affect bone health and bone density and make them more fragile, so making sure that the boys are getting adequate calcium and Vitamin D in their diet or supplements is also very important,” added Dr. Smith.
Another side effect of steroids is delayed puberty. This can have added psychological implications for a boy already facing several challenges.
“To these boys who are already shorter than their friends because of the steroids and look much younger, it can impact their self-esteem. If testosterone replacement is indicated, that might help jumpstart puberty for the boy. That means an endocrinologist plays an important role, too.
“Endocrinologists are important in care because of the endocrine abnormalities that the steroids come with can suppress the adrenal glands, diminishing the boys' ability to produce steroids in times of stress or illness. Blunting that response potentially puts them at risk for more severe illness because of a lack of the ability to create their own body's steroid response to stress,” explained Dr. Smith.
However, one of the benefits of daily steroids is that the incidence of severe scoliosis has plummeted over the past 20 years. Researchers are not fully clear why this has happened, but they suspect steroids allow boys to walk a year, two, three, longer, and that they're upright during a period of growth in the spine
Supporting the family of boys with DMD is also important. Social workers are key links in providing important information and monitoring the psychological impacts that DMD families can face.
“If you leave our clinic feeling like your time was well spent or you're leaving the clinic with a piece of information that's actually really helpful on a day-to-day basis, that generally comes from our social worker. They educate the family or help them discover a new service that is available for the child, or something through school that they weren't even aware of that helps make the child's life easier on a day-to-day basis,” added Dr. Smith.
The roles of physical and occupational therapists in treatment provide a lot of practical assistance. Often, it is the therapist who must begin the discussion of how a DMD patient might benefit from attempting to be fully ambulatory to using a wheelchair.
Although a person might still be walking fairly well, they may be starting to not do certain things out of fatigue or fear of falling. Those can be difficult but necessary discussions that families must have at some point.
How Do I Prevent Duchenne Muscular Dystrophy?
For most families, the diagnosis of Duchenne Muscular Dystrophy comes as a surprise. There is nothing that someone did or did not do. About one-third of the time, the genetic difference that causes DMD occurs randomly, and there is nothing that could have been done to prevent it.
In the other two-thirds of cases, the genetic difference that causes DMD is passed down from a mother who is a carrier. Without the help of in vitro fertilization, there is no way for a mother to decide what genetic information is passed to her child. So in short, this is no one's fault.
If you are aware that you are a carrier for DMD, you can speak to a genetic counselor or physician about the process of IVF to see if it might be a good fit for your family. Alternatively, you could use eggs from a donor that does not carry the genetic difference in the DMD gene.
Prognosis of Duchenne Muscular Dystrophy
Until recently, boys with DMD usually did not survive past their teenage years. But advancements in respiratory and cardiac care have extended life, allowing boys to become adults who go to college, have careers, get married and have children. Survival into the early 30s is much more common among those with DMD.
“I think we've made great strides in care over the years which have prolonged life expectancy for these boys. The vast majority of them progressed from boys to men and are living in their 20s and 30s, some even longer than that with better cardiac and pulmonary care. So, improved care and better guidelines to guide the physicians who are treating Duchenne patients have been very helpful,” said Dr. Smith.
A Closer Look at DMD Clinical Trials
Clinical trials have also played an important part in developing effective therapies.
“Even though we don't have a cure or even really a treatment that significantly affects the natural progression of the disease, I think we're on the cusp of that. There's a lot of hope out there now, realistic hope, that maybe was not the case five or ten years ago,” added Dr. Smith.
DMD research and clinical trials may create a much larger footprint that could cure several conditions.
“I think that much of what we learn from clinical research and investigational therapies in Duchenne will truly translate over into many of these other genetic muscle disorders, and other genetic conditions. Just thinking about something like gene therapy or some of the other approaches that are being looked at.
“The trials may be in Duchenne muscular dystrophy right now, but we're already seeing these approaches being tested out in other muscle diseases. I think that a lot of the effort that's being expended and a lot of what we're learning as we try to come up with novel and really impactful therapies for Duchenne will be applicable to other muscular dystrophies as well,” said Dr. Smith.
Gene replacement therapy has gotten a lot of attention as a possible cure in the future.
Dr. Smith explained further, “Gene editing would be the CRISPR arm of gene therapy, where you actually edit, you cut out the mutation and maybe correct it, and maybe even allow the gene to make a normal protein.
“Those trials I think are imminent but I think they're still relatively a long way off from clinical trials in humans and in boys with Duchenne.
“Currently there are three gene replacement therapy trials that are ongoing in boys with Duchenne, and with that approach what you're doing is essentially packaging the Duchenne gene, although it's a small version of it called micro or mini dystrophin.
“The delivery truck for gene replacement therapy is something called a AAV, Adeno-associated virus shell. That shell is a virus that doesn't cause any known human symptoms or disease. The idea is to use that viral shell, also called a capsid, as a delivery truck. You package that delivery truck but it’s big enough to handle the entire Duchenne gene, so you have to cut down the Duchenne gene to its essential parts and hopefully that's small enough to package inside this AAV capsid.
“That delivery truck is really good, like all viruses, they get into all kinds of everything all over the body, including muscle tissue and heart tissue. The idea is, with a one-time intravenous infusion to deliver trillions of trillions of these viral particles that are loaded with their payload to the muscle. They get into the muscle cells, have the gene turn on in the heart and in the skeletal muscle and start making dystrophin. And that's happening!”
“We have published preliminary results from all three of the trials showing that you can do that. There are some safety concerns, but the amounts of dystrophin that are being seen are spectacular in my mind. There are amounts that I would be very surprised if we don't see a clear clinical benefit way above and beyond what we currently see with the standard of care treatment with steroids from gene therapy.”
What to do Next: Living with DMD
Thanks to a number of advancements in treatment, boys with DMD are living longer and more active lives than ever before.
It is important that families connect with a multidisciplinary clinic familiar with Duchenne Muscular Dystrophy. Regular visits to the clinic will ensure that the patients are being monitored according to guidelines and receiving the most up-to-date care.
The clinic will help families transition through the progression of the disorder and provide not only physical but mental support.
If someone with DMD is scheduled to undergo surgery, it is important that the surgeon is aware of the condition, as patients may have a poor response to anesthesia.
In addition to medical visits, regular exercise has been shown to be helpful in young patients by decreasing muscle contractures and decreasing atrophy. Additionally, Individuals with DMD should be exposed to sunshine and a balanced diet rich in vitamin D and calcium.
This will improve bone density and reduce the risk of fractures. Dietary supplements may be necessary after consulting with a dietician and an endocrinologist.
Families with DMD can also benefit from connection with support organizations. These organizations are often spearheading research on the path to a cure.
“CureDuchenne has spent the past two years really investigating how we're going to overcome the limitations of gene therapy so that all patients can have the promise of this potentially transformative treatment,” said Miller.
“We invested in 4D Molecular Therapeutics which is looking at alternative vectors. We invested in Chameleon Biosciences which is looking at a way to basically mask or hide the AAV vector so it can actually go in as a stealth treatment.
“More recently we're really excited about a very early stage project that we're funding. Myasthenic Therapeutics is using a non-viral delivery at the full link dystrophin, which is a really huge undertaking and it's a very lofty goal,” she added.
“We basically look at our job as identifying the most promising science projects and then going in with heavy, heavy betting with our scientific team, drug development team, and taking the risk out these early stage projects, which will then go on to get proof of concept in pharmaceutical and larger biotech companies.”
Overall, Miller remains optimistic. She and her team are in it for the long-haul that’s going to be required to overcome DMD.
“It’s early, but we think that we are basically circling the wagon around this disease and coming at it from every angle possible so that we can actually have a cure.”
Overall, several DMD therapies are currently in the works. The most promising include:
Gene therapy. Clinical studies are currently focusing on restoring dystrophin expression by administering recombinant adeno-associated virus vectors that deliver either functional dystrophin transgene or gene-editing components.
Gene repair. CRISPR (clustered regularly interspaced short palindromic repeats)-associated protein 9 (CRISPR/Cas9)-mediated genome editing in mice has been shown to partially restore dystrophin protein expression
Eteplirsen. Another investigational approach uses antisense oligonucleotides, such as eteplirsen, to induce specific exon skipping during pre-messenger RNA splicing and restoring dystrophin expression. Eteplirsen skips exon 51, inducing a dose-related increase in dystrophin production without drug-related adverse effects. The FDA granted accelerated approval for eteplirsen infusion in September 2016, making it the first drug approved to treat individuals with DMD. However, the FDA is requiring the manufacturer to conduct a trial to determine whether eteplirsen improves motor function of individuals with DMD with an amenable dystrophin.
Ataluren. 10-15% of individuals with DMD harbor nonsense (a variant in which a codon is changed from one that specifies an amino acid to one that specifies a termination) pathogenic variants. The investigational drug ataluren may treat this by promoting ribosomal read-through, allowing bypass of the pathogenic variant and continuing the production of a functioning protein.
Myostatin inactivation. The protein myostatin has an inhibitory effect on muscle growth. Without it, mice that would otherwise express the DMD phenotype have increased muscle mass compared with those with a wild type myostatin gene. Animals treated with antibodies to myostatin have increased muscle mass and strength, lower serum creatine kinase, and less evidence of muscle damage.
Cell therapy. Skeletal muscle progenitors continue to be investigated in the treatment of DMD. A promising technique in mice isolates and transplants muscle satellite cells, a natural source of cells for muscle regeneration.
Idebenone. A randomized controlled trial of the antioxidant idebenone showed significantly reduced decline in respiratory function as measured by peak expiratory flow and other pulmonary function tests.
Additionally, genetic counselors are a wonderful resource for families with Duchenne Muscular Dystrophy. They can serve as resources to better understand the genetics behind the condition, connect families to support, and help with family planning options.
For More Information
Parent Project Muscular Dystrophy
401 Hackensack Avenue, 9th Floor
Hackensack, NJ 07601 Toll-free: 1-800-714-5437
E-mail: email@example.com Website: https://www.parentprojectmd.org/
1400 Quail Street, Suite 110
Newport Beach, CA 92660 Telephone: +1-949-872-2552
E-mail: firstname.lastname@example.org Website: https://www.cureduchenne.org/
1300 Quail St, Suite 100
Newport Beach , CA 92660 Telephone: +1-714-801-4616
E-mail: Catherine@coalitionduchenne.org Website: http://www.coalitionduchenne.org
Muscular Dystrophy Association (MDA)
222 S Riverside Plaza
Chicago, IL 60606 Toll-free: 1-833-275-6321 (Helpline)
E-mail: email@example.com Website: https://www.mda.org
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Brenna: You are listening to the RareDisease Connection, a production of Aspect Health and raredisease.com. It's not until I get a cold that I realize just how much I take for granted the ability to breathe easily. Just like when you jam a finger or break an arm, you quickly become aware of just how much we use our hands. A loss of skill or regression is a phenomenon that's felt across some genetic conditions. Brenna: Today we're going to talk about Duchenne muscular dystrophy, the most common childhood onset form of muscular dystrophy. For these families, loss of ability is a reality and nothing is taken for granted. RareDisease Connection and our additional resources on raredisease.com and yourdna.com brings together the people whose expertise can explain what you're facing. From diagnosis to prognosis to treatment options, all the way to questions like, "Who do I talk to? Where are the people who've been through this before?" You'll find those answers here, from doctors, geneticists, academics, genetic counselors, patient organizations, other patients and their families, they're all within your reach and we're here to connect you. Brenna: This is RareDisease Connection. Hey, everyone. This is Brenna, cohost of RareDisease Connection and Director of Patient Education at yourdna.com. Today, I'm going to bring you conversations with three experts on Duchenne muscular dystrophy. Before we get started you should know that this podcast is just the beginning. We have taken the information from this podcast and added additional resources, explanations, links and references for you in the downloadable guide. You can get your free copy by going to raredisease.com/dmd. That's raredisease.com/dmd. Brenna: So let's get started. Our first guest today is Ann Martin, a certified Genetic Counselor and Director of the Duchenne Registry at Parent Project Muscular Dystrophy based in Hackensack, New Jersey. Thank you for taking the time to speak with us today. So why don't you start just by introducing yourself to us? Ann Martin: Okay. Great. My name is Ann Martin and I am a Genetic Counselor and Director of the Duchenne Registry at Parent Project Muscular Dystrophy. For those of you who are not familiar with PPMD, it is the largest, most comprehensive nonprofit organization in the United States that's focused on finding a cure for Duchenne. I've actually been with PPMD for nine years and prior to that I worked for 15 years as a clinical genetic counselor in a large hospital system. Part of my role there was providing genetic counseling to patients and families in the neuromuscular specialty clinic, so that was when I first started working with Duchenne families and began understanding the complexities of this disease. Brenna: So, speaking from your experience as a genetic counselor and then also with your work with the PPMD, when you hear Duchenne muscular dystrophy, what immediately comes to mind for you? Ann Martin: Well, Duchenne, like so many genetic disorders, is a devastating diagnosis for families to receive. The pediatric onset and the progressive nature of the muscle wasting and the historic lack of treatments, which fortunately is changing, but all of that combined make it so difficult for families, and I think what is even more challenging is the X-linked inheritance of Duchenne. So, you can have multiple children in a family affected and carrier females who have to deal with not only the psychological burden of knowing they are carriers, but sometimes physical manifestations of the disease as well. Brenna: So, while we have you and have your genetics expert, thinking a little bit about the genetic signed Duchenne muscular dystrophy, what's actually occurring that causes this condition? Ann Martin: Okay. Yes, so, Duchenne is caused by mutations or changes within the dystrophin gene which makes the dystrophin protein, and the dystrophin protein plays a critical role in the stability of the muscle cell membrane, so without dystrophin the muscle cells can easily degrade and this leads to the progressive muscle weakness and wasting that we see in Duchenne. Brenna: Is this a condition that's inherited? I know you mentioned X-link inheritance, so, what does that look like? Ann Martin: Yes, so the dystrophin gene is on the X chromosome, so Duchenne follows that X-linked inheritance pattern, but not all cases are truly inherited. About one-third or approximately 30% of boys who are diagnosed with Duchenne have what we call it de novo or a spontaneous gene change that occurs for the first time in them, so they are the first person in their family affected. The other two-thirds are approximately 70% of boys who are diagnosed with Duchenne did inherit the gene mutation from their carrier mother, but she may not have known she was a carrier until she had an affected child. Brenna: Thank you for going through the inheritance. When we think about that and think of the condition as a whole, are there certain groups that might be most likely to have DMD? What are the chances of having a child with this condition? Ann Martin: Well, Duchenne affects about one out of every 5,000 live male births. It can affect any races, given that X-linked inheritance of Duchenne, like you said, boys are much more likely than girls to be affected, and this is because girls have the second X chromosome with another copy of the dystrophin gene which basically acts like a backup copy. However, there are girls who can manifest signs of Duchenne and these girls are called manifesting Duchenne carriers, or females with dystrophinopathy. Ann Martin: Regarding the chances of having a child with Duchenne, if a woman carries the Duchenne or the dystrophin gene mutation, she has a 50% chance of passing it on to each child. So, if she conceives a boy, he will have a 50% chance of being affected with Duchenne, and if she has a girl, she would have a 50% chance of being a carrier like her mother. Brenna: Another thing that we often hear of when we hear of Duchenne muscular dystrophy is Becker muscular dystrophy. What's the relationship between these two conditions? Ann Martin: Yeah, that's a great question. Duchenne and Becker muscular dystrophy are actually both caused by mutations in the dystrophin gene, and they're sometimes referred to as the dystrophinopathies. If the mutation results in no dystrophin protein being produced, then usually the boy will have Duchenne, whereas if the mutation allows for some dystrophin protein production, then usually the boy will have a milder Becker presentation. And it's really easier to think of these diseases on the same spectrum, with Becker being at the more mild end of the spectrum, and Duchenne being at the more severe end of the spectrum. Brenna: So, moving into diagnosis, what are some of the common symptoms of DMD? Ann Martin: Well, Duchenne is characterized by progressive loss of muscle and this results in deterioration of not only the skeletal muscle but also the heart and the lung muscles. Most boys with Duchenne will need to use a wheelchair for mobility by, on average, 12 years of age, and many will die in their teens or 20s from cardiac or respiratory failure. But it's really important to point out that Duchenne isn't just a disease of the muscles, it actually affects almost every system in the body, and for this reason we do recommend that all individuals with Duchenne or Becker be followed at a multi-disciplinary clinic that specializes in Duchenne. And PPMD does provide certification to centers that provide the highest level of care for Duchenne, and we currently have almost 30 certified Duchenne care centers in the United States. Brenna: And so to find those centers, would they go to your website? Ann Martin: Yes. Exactly. They're all listed on our website in our care section. Brenna: Perfect. So I know you were mentioning mobility issues might require a wheelchair around age 12, but at what age does someone normally get a diagnosis? Ann Martin: Right, that's a good question. Boys are typically diagnosed between three to five years of age, but this can really vary considerably in the US and even worldwide. They usually present with trouble running or climbing stairs. They often have frequent falls. They can have enlarged calf muscles and sometimes even language delays in addition to the gross motor issues. Brenna: And so, going on that same line of diagnosis, there's clearly this physical signs and symptoms that you were mentioning. But what sort of test would a physician order to actually give someone this diagnosis? Ann Martin: Right. Well, the first test a doctor will usually order when he or she suspects muscular dystrophy is a blood test for creatine kinase or CK, and this is a marker of muscle cell degradation. So boys with Duchenne and Becker have extremely elevated serum CK values. And then if the CK is elevated usually the doctor will order genetic testing to confirm the diagnosis of Duchenne or Becker. There's several labs in the US that perform genetic testing of the dystrophin gene and many actually do this now as part of a neuromuscular gene panel. Ann Martin: In addition to the CK and the DNA test, sometimes doctors will order a muscle biopsy to actually determine exactly how much dystrophin is present in the muscles. But honestly, with our molecular technologies being so advanced today, muscle biopsies are no longer routine and are performed much less often than they used to be. Ann Martin: I also want to point out that PPMD is running a newborn screening pilot for Duchenne in New York State, and it is our hope that Duchenne will eventually be added to the newborn screening panel so that all affected children will be diagnosed soon after birth rather than having to wait several years for a diagnosis and endure a long diagnostic odyssey which so many families have to go through now. Brenna: Yeah, that's a common theme we've heard on several of our podcasts is that long diagnostic odyssey for so many families, and so I would imagine not only would it bring in answers sooner, but it would probably also help with treatment and care as they have an answer sooner so they could start management sooner. Ann Martin: Exactly. Exactly. That's our hope. Brenna: So, thank you for talking about all of those testing options for individuals who are postnatally, so are born already, but are there any prenatal testing available? I know you've talked about mothers being carriers and we've talked a lot about, on this podcast, carrier testing. So, are there options for diagnosis, though, prenatally? Ann Martin: Yeah. Definitely. There are several options for prenatal testing. If you have a family history of Duchenne or Becker and you know that you're a carrier, you can have the standard prenatal diagnostic procedures done. These include either chorionic villi sampling or CVS. That's done at the end of the first trimester, or amniocentesis in the second trimester. And both of these are truly diagnostic tests so they would tell you whether or not your baby inherited the Duchenne gene mutation. Ann Martin: A newer option that is just starting to become available is NIPT, which is non-invasive prenatal testing, and this is where a simple blood draw from the mother can be done to isolate fetal or placental DNA in the mother's blood stream. This can be done much earlier in pregnancy, but given that it is such a new procedure, it is still recommended to follow up with either a CVS or an amniocentesis. Ann Martin: Another option for women who are carriers would be to actually prevent the conception of an affected child, and this can be done by a technique called pre-implantation genetic diagnosis. In vitro fertilization must first be performed using the mother's egg cells and her partner's sperm cells, and then the embryos are tested for the Duchenne mutation and only the unaffected embryos are implanted back into the mother's uterus. And this technique is actually quite well established and it's been done for many years at several centers across the United States. Ann Martin: And I know I've been talking about women who know that they are carriers. I do want to mention that more and more women without any family history of Duchenne are finding out that they're carriers because Duchenne has been added to many of the universal carrier screens that are now offered to pregnant women or women who are considering pregnancy. So, if anyone is interested in learning more about carrier testing and prenatal diagnosis for Duchenne, I encourage you to reach out to the genetic counselors at PPMD or a genetic counselor in your area. Brenna: Thank you again for all of the information that you have provided and for spending time with us today. In closing, what's one thing that you wish everyone knew about Duchenne muscular dystrophy? Ann Martin: That's a great question. I think as a rare disease organization, one of our greatest challenges is raising awareness and really shining the spotlight on a disease that most people have never heard of, or even know how to pronounce. So, podcasts like yours really help to raise awareness and make our community feel a little less rare. And thanks to our organization and the amazing community of researchers and scientists that we work with, we have a rich pipeline of potential therapies and many promising clinical trials in the works. So, it's really an exciting time for Duchenne. Ann Martin: Our community is so passionate and over the last 25 years our voices changed not only the Duchenne landscape but the rare disease landscape. And through PPMD and our Duchenne Registry, we've helped to arm our community with the resources they need to truly effect change and become citizen scientists. Brenna: Ann, thank you for taking the time to tell us more about Duchenne muscular dystrophy. Whether you've interacted with a genetic counselor yet, or not, they play an invaluable role in the journey of anyone diagnosed with a rare genetic disease. If you have questions about Duchenne muscular dystrophy, I would recommend looking at nsgc.com to find a genetic counselor near you. Brenna: Our next guest is Dr. Edward Smith. Dr. Smith is a pediatric neurologist at Duke University Hospital who specializes in neuromuscular disorders. In addition to seeing patients, Dr. Smith is also involved in a number of clinical trials. Thank you for joining us today. So why don't you start of by telling us a little bit about yourself? Edward Smith: I am a pediatric neurologist by training, so I did pediatrics residency and then did several years of pediatric neurology residency training. And then I did an extra year of a fellowship in Neuromuscular Medicine. So that's the study of diseases of the muscles and the peripheral nerves, and Duchenne muscular dystrophy is included in that category and is one of the most common muscular dystrophies out there. Following my fellowship, I have been working at Duke where I did my residency of fellowship and I see approximately 150 Duchenne patients currently, and we have a very good, multidisciplinary clinic every Friday and that's where our patients will come in for clinical care, typically twice a year, more frequently if needed. Edward Smith: Beyond the clinical care I'm also involved in several clinical trials and that's been very rewarding and interesting, and it's been nice to be able to offer some of these trials to some of my families and patients as well. So, I'm a clinician and I'm also involved in clinical trials that are related to Duchenne. Brenna: So, thinking about your experience as a clinician and also as a researcher, when you hear Duchenne muscular dystrophy, what immediately comes to mind for you? Edward Smith: Oh, gosh, there's a whole flurry of things that come to mind, good and bad and everything in between. Obviously it's a diagnosis that nobody wants, nobody asks for. It's a devastating diagnosis. Duchenne affects boys. The gene, it's a genetic condition, and the gene for Duchenne is on the X chromosome, and boys have one X chromosome. So if they have a mutation on that gene, they don't have a second X chromosome or second gene to serve as a backup. So, it's considered a disease that affects boys. Edward Smith: There's some very, very rare exceptions to that, but generally it's a male disorder. I think that one of the hardest things, I'm a doctor but I'm also a father with two sons, and I think one of the hardest things is just watching the disease take away what these boys have gained, and typically the disorder is diagnosed around the age of four or five, maybe six, when the boys begin to develop clear weakness, clear muscular weakness. Prior to that there are more subtle signs of the weakness, things like getting up from the floor or climbing stairs, but it can be subtle and the diagnosis might be missed. Edward Smith: So boys with Duchenne, they are often a little bit late to walk but they do walk, and they gain motor milestones, but often a little bit delayed. The hard thing then is to watch that development plateau and then watch them lose those skills over time. I think of it like a blindness. What's worse? To be born blind or to have had several years of vision and have that vision taken away? So, not to be depressing, but that's the reality of it, and it's just a devastating diagnosis. Edward Smith: On the other hand, and this is more recently, a lot of hope comes to mind with the diagnosis. I think we've made great strides in care over the years which have prolonged life expectancy for these boys and the vast majority of them progressed from boys to men and are living in their 20s and 30s, some even longer than that with better cardiac and pulmonary care. So, improved care and a better guidelines to guide the physicians who are treating Duchenne patients have been very helpful. Edward Smith: And then there's, also, I mentioned clinical trials. There is also a lot going on from the standpoint of investigational therapies in clinical trials, some more promising than others. Some very promising, and we could talk about that a little bit. Even though we don't have a cure or even really a treatment that significantly affects the natural progression of the disease, I think we're on the cusp of that. I really do, and I think there's a lot of hope out there now, realistic hope, that maybe was not the case five, 10 years ago. So, yes, devastating diagnosis, devastating disease, but also with lots of hope. Brenna: I think that's probably something that's felt a lot across a variety of different rare diseases where they're working so closely with these families and they see so much of the complications that arise from different conditions. But then they're also, they are holding out hope working on treatments and management options, and so I think that's a sentiment that's likely felt across the rare disease community. Edward Smith: I agree, and Duchenne is certainly classified as a rare disease, but among rare diseases, it's not that rare, even though it affects only boys. It affects about one in 3,500, one in 5,000 boys, depending on the numbers that you use. So, that's not that rare in the rare disease world, and it's certainly not rare in the muscular dystrophy world. I think it's the most common muscular dystrophy in terms of incidents. Edward Smith: So, that in and of itself I think has helped fuel all the research. There's much more research, the clinical research, the basic science research, that's been done in Duchenne than in some of the rarer muscular dystrophies. And that's hard. That's difficult for those families and those patients who have those other muscular dystrophies that aren't seeing the same amount of effort put into their particular condition. But I think that much of what we learn from clinical research and investigational therapies in Duchenne will truly translate over into many of these other genetic muscle disorders, and other genetic conditions for that matter. Just thinking about something like gene therapy or some of the other approaches that are being looked at. Edward Smith: Yes, the trials may be in Duchenne muscular dystrophy right now, but we're already seeing these approaches being tested out in other muscle diseases. I think that a lot of the effort that's being expended and a lot of what we're learning as we try to come up with novel and really impactful therapies for Duchenne will be applicable to other muscular dystrophies as well. Brenna: So, going back, and you mentioned this is very common in the rare disease space, this is obviously an X-linked condition that's occurring the majority of time in males, but outside of that, are there certain populations that are more likely to have this condition? Either different races, ethnicities, locations in the United States or in the world? Edward Smith: Not to my knowledge. I believe you're a genetics counselor so you may know something I don't know, but I think worldwide the incidents is similar. Now, life expectancy will vary from country to country depending on standards of care and just access to medical care. As the boys get older into their teens there begins to be a noticeable decline and pulmonary and cardiac function, not just the skeletal muscle strength and the skeletal muscle function. So, it's very important to recognize those issues early on and treat as preemptively as you can with the various medications and respiratory modalities. Edward Smith: Standards of care differ across countries and outcomes differ across countries. But the incidences, as far as I how, they're similar worldwide. The Duchenne gene is... I don't know if it's the largest, I've read that it's the largest. If it's not the largest, it's very close to the largest gene in the entire human genome, and it has areas on the gene that are prone to mutation. So it's not only a giant gene with lots of opportunity for mutation, but it's also got hot spots on it where mutations tend to happen along the gene. Edward Smith: Many of the patients who have Duchenne have absolutely no family history of it. We think of it as an inherited condition. It's a genetic condition. But probably about a third of patients will have no family history, and if you test their mother who you would think would be a carrier for the mutation and carry a mutation on her X chromosome, there's about a 30% chance you won't find that when you test her. So the point to make with this is that Duchenne, even if we have treatments early on, or even if we could identify every carrier mother and provide genetic counseling before she becomes pregnant, there are still going to be a large number of cases that occur just spontaneously. Edward Smith: So I think Duchenne is with us as long as there are humans on earth. There are other conditions that are like that as well, but Duchenne has a very high spontaneous occurrence as well, and it's unfortunately here to stay because of that. Brenna: So thinking about the patients that you see, you've probably made several diagnoses of this condition. What can a family expect when they come in for that initial exam? Edward Smith: This is a tough question to answer because I think that there's often a different answer for each family. The way I approach that first visit where I give them the diagnosis, my goal with that visit is to give the family the information, let them know very clearly what this means from the standpoint of the diagnosis and the prognosis. And then do everything I can to help the family, the parents, understand that they're not alone and I think that this is something that comes up, for obvious reasons, in all rare diseases, but particularly just devastating rare diseases. Edward Smith: The chances are this family had never heard of the diagnosis of Duchenne muscular dystrophy, or if they did it was very recent. And if they did do some research ahead of time, who knows what they found on the internet? It's not going to be good news and there's no way to make it good news. It's important, in my mind, to be very honest about that fact, but then to help the family understand that, yes, I'm a doctor and this is a clinic, but our primary role is to support the family through this, and that first visit and the weeks following that first visit, in my experience, are the toughest. Edward Smith: It's almost like losing a child. Everything, all the hopes and expectations you have for that child are now being severely altered and you have no control over that. So I think just understanding first and foremost that you have a team of doctors and support to have in a clinic that are here to help you and help your child understand that they're not alone and that they're supported, that's my primary goal in that first visit. But then throughout the care span, the span of care, this disease progresses with time, so needs change with time. I think it can be very helpful to be able to provide anticipatory guidance as much as possible. Edward Smith: I think that the milestone of losing the ability to walk, that's a huge one that a lot of families understandably fear, but many of my patients are not ambulatory now but they're living very good lives. It's a challenge to help families understand that and this doesn't happen overnight, you kind of grow into it, but losing ambulation and then ultimately losing some of the independence that hand and arm function provide with activities of daily living, for instance. So, that all occurs on a spectrum and over time, and I think that one of my roles as the treating physician is to make sure that families and patients are aware of this. That in the absence of a truly disease-altering, disease-modifying therapy, we can expect this and, what are we going to do about it? How are we going to plan for it? And what do we have in the way, particularly, of technology but also physical therapy, occupational therapy support to help compensate for those losses in the progression of the disease. Edward Smith: There's a lot out there, technologically, there's a lot out there in particular that can be helpful. The big challenge there, though, to be honest with you, is often accessing that technology and paying for it. Many of the... they're expensive technologies, and many of the insurance providers simply won't pay for those technologies unfortunately. Brenna: So staying on that path in terms of treatment and management, when someone receives a diagnosis, what sort of evaluations should they be having? What sort of team members should they be seeing in terms of physicians? Edward Smith: That's a really good question. There are care guidelines that were developed by the CDC, the Centers for Disease Control, in tandem with a large patient advocacy group called Parent Project Muscular Dystrophy, PPMD, and the first version of those were published, oh, gosh, I believe it was 2009, and then were updated here recently, a little over a year ago. That's a great start because that document lays out what good Duchenne care should look like. Not all clinics are able to offer all of that, especially not in a coordinated fashion, but there are some key team members so any child or adult for that matter, with Duchenne, should have access to certain specialists. Edward Smith: Number one would be, I think, a neurologist like me. Ideally a neuromuscular neurologist but there are very few of those in the country, so sometimes a Duchenne clinic might not be run by a neurologist. It might be run by a pediatric cardiologist, or even a pulmonologist, or a physical medicine and rehabilitation doctor. So it doesn't have to be a neurologist, but you need someone who understands what Duchenne muscular dystrophy is and understands the need for multidisciplinary care, whether it's truly coordinated care or just separate visits to separate doctors. Edward Smith: One key member of the team is the pulmonologist. Typically, we have our boys begin to see the pulmonologist by the age of five or six, and that's really just to begin to establish a rapport with that doctor and begin to learn what pulmonary function testing looks and feels like. I tried to do a pulmonary function testing once, not that long ago, and it's not easy, so asking a five-year-old boy to do that is also not easy. But you can gain some interesting and helpful information. And that's going to be a very important parameter to follow over time. There's a fairly well-described and expected decline in pulmonary function that occurs beginning at around eight or nine years of age and progresses each year. Edward Smith: So the pulmonologist is a very important member of the team. A cardiologist is also extremely important. The role of the cardiologist in Duchenne care is... And when that care should begin is debated by some, but in our clinic at least, similar to the pulmonologist, we have our children, our boys, see cardiologists, or our clinic cardiologists quite early, by five or six years of age, well before there should be any heart disfunction. But again, these are folks who can also help with the anticipatory guidance and offer support, and starting that sooner rather than later I think is a very helpful thing. Edward Smith: Another key team member is our nutritionist. The standard of care therapy, currently, for Duchenne, for all boys with Duchenne, is corticosteroids, glucocorticoids like prednisone or another one, a different one called deflazacort, very similar, and those come with a lot of side effects, in particular weight gain, but weakening of the bones and short stature and many other things. But weight gain is a tremendous issue and is largely related to the steroids in many of the boys. So, the steroids are used as treatment because they have been shown to slow progression a little bit. Not halt progression, but slow progression and delay the age at loss of walking ability by a couple of years, so the boys still head in that direction but just more slowly. And, likewise, slow the progression of weakness in the upper extremities, the arms and the hands as well. Edward Smith: So that's the benefit of steroids, but they come with huge side effects, and weight gain is part of that. So our nutritionist or dietician in clinic is very important, and is a very important source of information for families. Increased weight requires more effort to move around, and if your muscles are weak or getting weaker, that can impact your ability to function. The steroids also can affect bone health and bone density and make them more fragile, so making sure that the boys are getting adequate calcium and Vitamin D in their diet or supplements is also very important. Edward Smith: The endocrinologist, many clinics will have an endocrinologist for similar reasons, because of the endocrine abnormalities that the steroids come with, suppressing the adrenal glands and making the boys' ability to produce steroids in times of stress or illness, blunting that response and potentially putting them at risk for more severe illness because of a lack of the ability to create their own body's steroid response to stress. Edward Smith: Delayed puberty is expected with steroids. As a dad of two teenage boys, that may actually sound kind of attractive, but to these boys who are already shorter than their friends because of the steroids and look much younger, it can impact their self-esteem. And if testosterone replacement, for instance, is indicated, that might help jumpstart puberty for the boy. So, the endocrinologist plays an important role. Edward Smith: One other really key person to our Duchenne care team is a good social worker. I often tell families that I think if you leave our clinic feeling like your time was well spent or you're leaving the clinic with a piece of information that's actually really helpful on a day-to-day basis, that generally comes from our social worker who has educated the family or discovered a new service that was available for the child, or something through school that they weren't even aware of that helps make their lives easier, make that child's life easier on a day-to-day basis. Edward Smith: The other folks who are very helpful in that way and, again, if the family leaves and feels like their time in clinic, and it's a long time, these visits are half-a-day to six hours, if they're driving home and feeling like that was time well spent, it's often because of the time they spent with the occupational therapist and the physical therapist. And that can be a challenge outside a clinic, to secure regular physical or occupational therapy appointments, but in our clinic our therapists, and any Duchenne clinic, for that matter, the therapists generally have a very good knowledge of Duchenne and other muscular dystrophies and how they impact the patient. Edward Smith: I spoke a little bit earlier about different technologies and different orthotics that can be offered to help delay or postpone things like the progression of joint contractures. But also, the therapist can really help begin that discussion at the appropriate time of, "You know, I think your son might benefit from a manual chair now for longer distances, or possibly even a powerchair, even though he's still walking and walking quite well, maybe he's not doing things he would otherwise do because of fatigue or a fear of falling and injury, and maybe having a wheelchair," and beginning that discussion at least makes sense right now. Those are very difficult discussions and again it gets to that idea that losing ambulation for obvious reasons is something to be avoided at all costs. Edward Smith: But I think in retrospect I found that most of the families who did eventually choose to pursue a powerchair, in retrospect, many of them wished they had thought of that or done that earlier. So, that's part of our role, is to provide that anticipatory guidance. And so that sums up the team. Some clinics will also have an orthopedic surgeon as a regular team member. We have orthopedics as needed. A lot of that has to do with the joint contractures that I just mentioned at the heels or the ankles, and at the knees in particular. And also because of scoliosis, the scoliosis used to be a tremendous problem in Duchenne and it was almost a given that most boys would develop significant scoliosis over time which can impact mobility, it can impact breathing. Edward Smith: With the introduction of steroids, daily steroids, over the past 20 years or so, that incidence of severe scoliosis, for reasons that are still somewhat unclear, the incidence of severe scoliosis has plummeted. And it may have something to do with the steroids allowing the boys to walk a year, two, three, longer, and that they're upright during a period of growth in the spine, so it's not well understood, but scoliosis is not as big of an issue as it used to be, at least not in clinics or countries that are using daily steroids. Brenna: So, thinking about this coordinated team effort, the advances that you've seen, you've mentioned that life expectancy has increased or gotten longer in the more recent years. Staying on that track, are there any new treatments and therapies that are coming or being developed that you're excited about? Edward Smith: There are several. Actually, there's more than several. There are a bunch [inaudible 00:40:25] and it makes it really difficult to discuss because there's so many. I think one helpful way to think of it is to group them by what's their approach to the disease, to Duchenne. So let me back up for just a second. So what causes Duchenne? Well, Duchenne is caused by a mutation in a gene called the DMD, Duchenne muscular dystrophy gene that's on the X chromosome. That gene is, like all genes, it's a recipe for, instead of a cake, it's a recipe for a protein called dystrophin. And dystrophin is a large protein that helps protect the muscle. Our muscles are constantly being injured by regular physical activity, by exercise, by vigorous exercise, weight lifting, our muscles are constantly being injured and they repair themselves. Edward Smith: When you have Duchenne, your muscles cannot produce any of this dystrophin protein. I don't know if this is a helpful analogy or not, but a lot of times people think of dystrophin like, if you think of a trampoline, around a trampoline, and think of the fabric on the trampoline as the muscle fiber. Think of those strings as the dystrophin, and then they attach to the frame on the trampoline, or you could think of that as another muscle fiber or part of that muscle bundle. So, in Duchenne, your springs don't work at all, or, actually, in most cases, there aren't any springs, and the fabric, the muscle, the trampoline doesn't work, first of all, i.e. you're weak, and secondly, the fabric eventually tears and can't repair itself. Edward Smith: So the muscle, without dystrophin, can't recover fully from normal injury and over time that injury accumulates, and what that looks like is gradual weakness because you have less functioning muscle and an increase in scar tissue and fat replacement and fibrosis in the muscle over time. So, different approaches to treating the condition, steroids are used because they seem to reduce some of the inflammation in the fibrosis or scarring, reduce it or slow it down, all right, and allow the muscle to stay healthier longer, and therefore stay stronger longer. But again, they come at a cost. Edward Smith: So, the treatments that are being looked at that are in the research or clinical trials pipeline approach Duchenne from different angles, and one is, and I think the most promising in my mind, approach, is to just, could we... How do we replace the dystrophin? Could you somehow help these boys and help their muscle make the missing dystrophin protein? So those are called dystrophin replacement strategies and they come in different flavors. There are two FDA-approved treatments for Duchenne muscular dystrophy that are considered dystrophin replacement treatments. The current versions of those leave a lot to be desired. They do help the boys' muscle make a very small amount of a partial dystrophin, it's not a full, normal dystrophin. Edward Smith: And the jury is still out on whether or not treatment with that particular approach has clinical benefit or not. But they have been approved and they're prescribable. Unfortunately, those treatments, each one of them are only applicable to a small fraction of the boys with Duchenne. It depends on their particular mutation. So, even if they were really, really helpful, they'd only be applicable to probably eight to 10% each for boys with Duchenne. Edward Smith: Another approach that is, I think, in the news a lot right now is something called gene replacement therapy, or gene therapy. I think using the term gene therapy is good, and then you have to decide, are we talking about gene editing now? And I think everyone, many people who listen to this podcast will have heard of CRISPR? So, gene editing would be the CRISPR arm of gene therapy, where you actually edit, you cut out the mutation and maybe correct it, even, and maybe even allow the gene to make a normal protein. Edward Smith: Those trials I think are imminent but I think they're still relatively a long way off from clinical trials in humans and in boys with Duchenne. Currently there are three gene replacement therapy trials that are ongoing in boys with Duchenne, and with that approach what you're doing is essentially packaging the Duchenne gene, although it's a small version of it called micro or mini dystrophin. I told you that the Duchenne gene cell is incredibly large. The delivery truck for gene replacement therapy is something called a AAV, Adeno-associated virus shell. So, that shell, this is a virus that doesn't cause any known human symptoms or disease. And so the idea is to use that viral shell, also called a capsid, as a delivery truck. So you package, that delivery truck is kind of small, though, and it's not big enough to handle the entire Duchenne gene, so you have to cut down the Duchenne gene to its essential parts and hopefully that's small enough to package inside this AAV capsid. Edward Smith: And so, we're there, right? There are currently three programs, two that are active and one that's on hold. They all vary a little bit but they use AAV as the delivery truck and they vary in their gene a little bit, but they package the gene. And so the idea is, that delivery truck is really good, like all viruses, they get into all kinds of everything all over the body, including muscle tissue and heart tissue. And the idea is, with a one-time IV, in a vein, intravenous infusion, to deliver trillions of trillions of these viral particles that are loaded with their payload to the muscle, and have that get into the muscle cells, have the gene turn on in the heart and in the skeletal muscle and start making dystrophin. And that's happening. Edward Smith: We have published preliminary results from all three of the trials showing that you can do that. The jury's still out on safety. There's some safety concerns, but the amounts of dystrophin that are being seen are spectacular in my mind. There are amounts that I would be very surprised if we don't see a clear clinical benefit way above and beyond what we currently see with the standard of care treatment with steroids from gene therapy. So, there will obviously be better versions of these down the road that are more effective and safer, but I remain very hopeful that gene therapy programs, specifically the gene replacement programs, will continue in Duchenne. And this approach, again, as I mentioned earlier, this approach is being used, investigated in other genetic conditions as well, so what we learn from the immune response to this treatment, for instance. Edward Smith: That's one of the risks is that the body's immune system is not going to like this, but what we learn from the immune response in the Duchenne trials will translate over into these other trials as well. So those are the highlights of the dystrophin replacement strategies, and that again, are at the top of my list for what do I think is going to be most effective. Edward Smith: And then there are other treatments that address what we think of as the downstream effects, the fibrosis, the scarring, the inflammation, and there are several active trials right now looking at compounds that could help with that. Anyone who treats Duchenne and any parent and generally any child on steroids, on daily prednisone or deflazacort, would gladly trade that drug in for something else that works similarly well but without the side effects. So, alternatives to the current corticosteroid regiment are being looked at as well. And then some others, looking at improving heart cardiac function, specifically, or breathing pulmonary function specifically. Edward Smith: But I think that, if you just go to the root of the problem, the lack of dystrophin, my hope is that with something like a gene replacement therapy approach, those other downstream problems will, maybe not entirely go away, but they'll become much less of a factor over time. So, lots going on in the research clinical trials world for Duchenne, and it's extremely exciting. Brenna: Thank you for taking the time to go through all of those. I know it's probably a lot to keep straight and a lot to express to your patients that you see. And thank you for spending time with us today. Just in closing, I would like to ask what your best advice would be for a parent or a loved one or an individual with Duchenne muscular dystrophy who might have been recently diagnosed. Edward Smith: Well, my advice would be to try to find a clinical care team that understands Duchenne, is knowledgeable with Duchenne, and try to access that clinic. There are networks of clinics. A large network, of course, is the Muscular Dystrophy Association in general. If you could go through an MDA clinic you really should be seeing people there who are quite familiar with Duchenne. I mentioned Parent Project Muscular Dystrophy. They have a network of certified Duchenne care centers around the country, and you can find them on the internet. Even if you only go there once a year, because of distance or something, that might be a very good way to spend the time even if it's just once a year, and that team could communicate with your doctors locally. Edward Smith: Most importantly, I think, be hopeful, and that hope is realistic. I don't think it's rose-colored glasses. There is just so much that we're on the cusp of. And don't feel alone, because you're not. There are thousands of Duchenne patients just in the United States and depending on what your comfort level is as a parent, as a family, I would really encourage you to reach out to other families. The doctors, including myself, I can't identify with you on that same level, but establishing contacts with other families and other patients can be tremendously rewarding and nurturing and supportive. So that's, I think, what I would encourage above all. Brenna: Thank you Dr. Smith for spending time with us today. If you have a loved one who was recently diagnosed with Duchenne muscular dystrophy, it is important that you identify physicians familiar with this condition. You can go to parentprojectmd.org to see a list of specialty clinics. Brenna: Our final guest today is Debra Miller, the CEO and Founder of CureDuchenne. Prior to her son's diagnosis in 2013, Debra had never heard of Duchenne muscular dystrophy but her passion and business experience led her to found and lead CureDuchenne. Thank you for sharing your story with us today. So why don't you start off by just introducing us to you a little bit? Debra Miller: Sure. My name is Debra Miller and I'm the CEO and Founder of CureDuchenne. We started this organization back in 2013 when our son, Hawken, was diagnosed with Duchenne muscular dystrophy. At that point we had never heard the word Duchenne, didn't know anything about it, and were just completely shell-shocked as most parents are when they get this diagnosis. So we did investigation and we really looked for an organization knowing that we were going to want to be active to raise funds and try and find a cure, and really couldn't find an organization that focused on research and had a real sense of urgency, and we obviously had a base sense of urgency. Debra Miller: So we started CureDuchenne. I don't have the medical or scientific background but definitely the mother's passion and a lot of business experience, and different nonprofits are started by founders, I think, who fall back on their previous experience to lead them in the direction that they're going. And from my husband and myself, applying some business practice to CureDuchenne, seemed the best way to get the science out of the labs and into clinical trials. Brenna: I absolutely agree and I think you're not alone, either. I've spoken to several advocacy groups that are ladder funded and started in the beginning due to a personal connection, either a child or a loved one, and so I think having those individuals as leaders, and so having a lot of fighting power behind them because they know how to rally those communities. Debra Miller: Mm-hmm (affirmative). Definitely. Brenna: So, let's talk a little bit about CureDuchenne. I've had the opportunity to look at your website which was so impressive. I recommend everyone go out and look at it. You have a Biobank, you have a clinical trial information, there's a bunch of resources, ways to get involved with your community, it's all really impressive. Can you tell me a little bit about your organization beyond that, maybe something you're excited about, initiatives you have. Debra Miller: Sure. So, and again, I could talk about CureDuchenne all day long. But, just to drill down, we started off primarily as a research organization, as I mentioned, and knowing that we were going to fund research that would hopefully make it through the clinical trial process and the companies would actually be delivering the patients, it made sense to us that if we were going to go to our donors and ask them for donations for CureDuchenne, that if there was a commercial return some day in the future because of our work, that some of that money would come back to our organizations so we could continue to fund more research, instead of just going back to our donors while the pharma companies were reaping all the rewards. Debra Miller: And so we were really one of the very early Venture Philanthropy models. The term was just being developed at that point. And so we were very fortunate and then we made a couple of early investments in companies that took a long time back then, but they were bought out by another company, so we invested in a small company called Prosensa that was bought out by BioMarin. From that one return we were able then to fund five more research projects, and from the returns from those research projects we were able to fund five more research projects. So out of one investment we've been able to parlay, gosh, 15 different research projects. And so we're obviously very grateful to the original donors who enabled us to do this project. Debra Miller: And so we continue to build on that and fund in early stage science. We basically look at our job as identifying the most promising science projects and then going in with heavy, heavy betting with our scientific team, drug development team, and taking the risk out these early stage projects, which will then go on to get proof of concept in pharmaceutical and larger biotech companies. Then they come in and invest the hundreds of millions of dollars that it takes to actually get a drug to the market. Debra Miller: So that's the basis of CureDuchenne, and along the way we realized that drug development takes a long time and that we needed to do something to take care of the kids while we were developing these drugs, so we started the CureDuchenne carers program. And that has grown into just an incredible resource where the pioneers are basically taking best care practices on the road to the patients and their communities because there just weren't that many physicians who really understood how to treat patients with Duchenne, especially physical therapists, because there are some nuances to treating Duchenne patients that a lot of PTs did not know and you can actually do some harm instead of good. Debra Miller: So we would send our PTs out with our scientists and meet families on there and in their communities, where they were able to really bring care to them. So it's blossomed to be just an incredible program. And then, from there, it's grown into, we have an annual national conference call, FUTURES, and last year we had about 600 people there and it was a festival of hope, basically. A lot of information but a lot of hope, also. Brenna: That's amazing. Just sitting here listening to how many angles that you have, work to make sure not only that there is research and funding and initiatives and that, but then also to make sure it's going back directly to the patients and their families, and meeting them where they are, it's really just inspiring to hear you talk about all of the different ways that you're... I don't want to say attacking those problems, but working with all of the different assets to this condition, it's really amazing. Debra Miller: Yeah. We pride ourselves in being problem-solvers so that as the science is progressing, as their knowledge of the disease is progressing, there's great progress but at each step you find gaps and holes. And so I think we've been really successful at identifying those gaps and being very nimble in being able to fill those gaps quickly. Brenna: So is there anything right now that you would say either your organization needs or is a big need in the DMD community as a whole? Debra Miller: As you know we started the CureDuchenne Biobank, and this was a huge gap, but there are some biobanks, but they are not open access. And so we wanted to make sure that we did not have any special interest involved with our Biobank, and that we wanted to make sure that we would, once we gathered these samples and are able to do the analysis on it, that we were able to offer it up to all researchers instead of just certain researchers. This is something that I think it's going to really help the research community because there's so much more we need to learn at a genetic level about this disease. Debra Miller: And so, if we can find modifying genes, different targets, what makes one patient progress much faster or slower than the other, it just opens up opportunities to treat this disease. So we're really excited and we feel that we really can offer this service to the researchers but ultimately this is something that the Duchenne community is going to benefit from. This is an education process, although I have to say that the response from the families has been tremendous in wanting to sign up and have their boys participate in this. Brenna: So, for individuals who are maybe just finding out about CureDuchenne, where would be the best place for them to go or the best person to contact to find more about the Biobank or just different ways to get involved? Debra Miller: I think the best way would be to send me an email directly. That's Debra, D-E-B-R-A, @cureduchenne.org, and I'll be able to direct them to the right team members within CureDuchenne. Brenna: So while I have you with me today, is there any events or resources outside of what you've already mentioned that you would like to highlight for our listeners? Debra Miller: Sure. There's a couple of things. First of all, we've pivoted to virtual events this year as many organizations have. We have everything from coffee talks to webinars to larger events that are very useful for the Duchenne community, dealing with COVID-19, dealing with age-specific needs of the Duchenne community, so look at our website or our Facebook page and you'll be able to see those different events. Debra Miller: We also are in the midst of our gene therapy initiative, and we have funded very exciting gene therapy over the past few years, and we were pleased last Friday just to see that one of our early investments that was bought by Pfizer is going into a phase 3 trial now. Very excited about that. There's such a huge promise with gene therapy, but again, there's gaps and problems with that, and unless you're a very young boy and you don't have an immune reaction to the AAV vector, you're going to be excluded. Debra Miller: And so CureDuchenne has spent this past year or two years really investigating how we're going to overcome the limitations of gene therapy so that all patients can have the promise of this potentially transformative treatment. So we invested in 4D Molecular Therapeutics which is looking at alternative vectors. We invested in Chameleon Biosciences which is looking at a way to basically mask or hide the AAV vector so it can actually go in as a stealth treatment. And more recently we're really excited about a very early stage project that we're funding which is Myasthenic Therapeutics which is using a non-viral delivery at the full link dystrophin, which is a really huge undertaking and it's a very lofty goal, and again, very early but it's really, I think, showing our commitment to gene therapy and developing very transformative therapies for this disease. Debra Miller: Also, we believe that cure for Duchenne is actually going to be a combination of a lot of different therapies. And so, as much as we're committed to the gene therapy initiative that we started many years ago, we understand that there are other really promising technologies. So we've seen actually two drugs be approved for exon skipping, which is not a cure but it's an ongoing treatment that has shown some promise to restore the protein dystrophin that's missing. And so we more recently invested in a company called Dyne Therapeutics which is using an antibody to deliver targeted therapeutics into muscle. And again, we're really excited about the team, about this technology. It's early, of course, which is what we do, but we think that we are basically circling the wagon around this disease and coming at it from every angle possible so that we can actually have a cure. Brenna: I absolutely agree. I think that's clear from all of the different... Just like you said, the different angles that you're taking this, and I think that's something that a lot of different rare disease models have to look at and experience as well. Brenna: So, in closing, again, thank you so much for spending time with us today. What is one message that you would like our listeners to leave with, either about Duchenne muscular dystrophy or your organization, CureDuchenne? Debra Miller: At CureDuchenne we do believe that we will cure Duchenne, and how fast and how many patients we save depends on funding and the community coming together to engage in our Biobank and all of our other initiatives. Brenna: Thank you, Debra, for sharing with us today all of the amazing things happening at CureDuchenne. If you are interested in getting involved, you can go to their website, cureduchenne.org, to learn more about the opportunities and connect to the community and support their mission. Brenna: I want to thank all of you for joining us today as we explore Duchenne muscular dystrophy. We had the chance to hear from three amazing experts, but it's only just the beginning. We have taken all of today's information and included it in a free downloadable guide. You can get your free copy by going to raredisease.com/dmd. We would love to connect with you. If you need someone to talk to, we're standing by. Go to raredisease.com/help. We're waiting for you. Rare Disease Connection is a production of Aspect Health and raredisease.com. Thanks for joining us.