Dystrophin Deficit, A Closer Look at Duchenne Muscular Dystrophy (DMD)
DMD is a progressive neuromuscular disease caused by a mutation in the dystrophin gene and is the most common severe hereditary myopathy  . Patients with DMD lack functional dystrophin protein in their muscle tissue, leading to progressive muscle weakness and often a reduced lifespan .
Duchenne Muscular Dystrophy (DMD) is an X-linked disorder that affects about 1 in 3,600 assigned male at birth, XY chromosome, live-born infants . DMD is caused by a mutation in the dystrophin gene, which damages the body’s ability to produce a protein called dystrophin . Figure 1 shows a comparison of sections of healthy skeletal muscle tissue and dystrophin-deficient skeletal muscle tissue. Dystrophin is essential for maintaining skeletal and cardiac muscle cell structure and function . When dystrophin protein function is compromised it causes progressive loss of the patient’s muscle tissue and function . This muscle loss leads to muscle weakness and loss of daily functions. At this time, there are treatments available to address the symptoms of DMD, however, a cure for all DMD patients has not yet been found.
Tell Me About this Rare Disease Genetic basis: DMD can be inherited in an X-linked recessive manner or may occur as a de novo mutation (about 1 out of every 3 cases) within the dystrophin gene . Figure 2 shows how an X-linked disorder like DMD can be inherited in a recessive manner. The dystrophin gene is located on the X chromosome (locus Xp21.2) and is one of the largest genes identified in the human genome with 2.6 million base pairs and 79 exons . This gene codes for the dystrophin protein, which is necessary for muscle contraction and relaxation . There are thousands of identified mutations within this gene that can cause DMD, all of which lead to a lack of dystrophin protein or a mutation within the protein that inhibits the protein’s necessary functions within skeletal muscle and cardiac muscle cells . There are multiple kinds of mutations that can cause DMD, with 60-70% of DMD mutations being large deletions, 10% of DMD cases being caused by large duplications, and 15-30% caused by point mutations or other small nonsense mutations . It is important to note that DMD is not the only disorder that can manifest from mutations within this gene- Becker muscular dystrophy (BMD) can also occur . BMD presents itself with milder symptoms that appear at a later age than DMD due to these patients having higher amounts of dystrophin protein (about 10-40% of the normal amount) compared to DMD patients who have almost none .
Clinical Presentation: Patients with DMD have less healthy dystrophin protein, which causes varying degrees of progressive skeletal and cardiac muscle weakness. This muscle weakness and atrophy typically begins in the pelvis and legs, with initially less severe muscle loss in the arms and neck . This muscle atrophy can cause difficulty walking or climbing stairs, frequent falls, a waddled gait, toe walking, calf muscle hypertrophy, fatigue, scoliosis, and a shorter stature  . Other related symptoms often include cardiomyopathy, breathing problems and shortness of breath, cognitive impairments, learning difficulties, delayed speech, and developmental delay . In infants, early signs of DMD may also involve the child having a hard time lifting their head (due to a weaker neck), not walking by 15 months of age, walking with legs far apart, using the Gower’s Maneuver, or walking with their chest pointing out .
DMD is a progressive disorder, meaning that after the patient begins experiencing symptoms, these symptoms will worsen over time. The progression of this disease differs between patients; however, most will experience a life-threatening cardiac and/or respiratory condition by the time they are 15 years old .
Incidence: DMD is the most common severe hereditary myopathy, with 1 in 3,600 assigned male at birth, XY chromosome, live-born infants affected .
1830: Sir Charles Bell described a case of a patient with muscle weakness in their lower extremities, the first historical account of muscular dystrophy .
1858: Guillaume Duchenne de Boulogne saw his first DMD patient in his clinic and over the next several years wrote and published about several similar cases .
1987: The dystrophin protein was first identified by Louis M. Kunkel .
2001: The first Senate hearing focused on DMD took place and later this year, the MD-CARE Act passed to establish centers of care and accelerated research for muscular dystrophies .
2016: The first DMD targeted treatment, Exondys 51 (eteplirsen), received accelerated approval from the FDA . This approval was controversial but was considered a win for patient advocate groups .
2023: The first gene therapy treatment for DMD, Elevidys (delandistrogene moxeparvovec-rokl) received accelerated approval from the FDA .
The State of the Disease Today: Standard of care for patients with DMD typically involves a specialized team dedicated to treating the physical symptoms and psychosocial aspects of the disease. This team varies across patients but may include physicians, nurses, physiotherapists, speech therapists, dieticians, psychologists, occupational therapists, and social workers . Physicians may emphasize cardiac, respiratory, orthopedic, endocrinological, gastrointestinal, urological, and neurodevelopmental/neuropsychological care, as management in these areas can increase the patient’s quality of life and lifespan .
In recent years, there has also been a boom in gene-targeting therapeutic research, with the first gene therapy to treat DMD, Elevidys, receiving accelerated approval from the FDA just this year (2023)  ! This drug is administered through a single intravenous dose and aims to improve motor function in patients by allowing the body to produce functional micro-dystrophin . However, Elevidys is only approved for certain pediatric patients between 4-5 years old based on data that demonstrated increased expression of the micro-dystrophin protein in patients within this age range . A clinical study is ongoing to assess the clinical benefit of the drug across the DMD population . Meaning, although this drug is a step towards a cure, it does not cover the needs of all DMD patients right now. Other therapeutics such as exon skipping antisense oligonucleotide therapies are also available but, similarly, only are applicable to a small subset of the DMD population. However, we remain hopeful as there are over 10 different therapeutics to restore or replace dystrophin currently in clinical trials .
What is it like to be a patient with this disease?
Who are the patients? Since DMD is an X-linked disorder, those assigned male at birth (having one X and one Y chromosome) are the demographic most likely to experience symptoms of DMD as the result of an inherited or sporadic mutation within the dystrophin gene  . Patients typically start showing recognizable symptoms around 2-4 years old, however, some symptoms can be identified as early as infancy or may be noticed later in childhood . Due to this range, the average age for a DMD diagnosis is around 4 years old . Due to recent medical advances in cardiac and respiratory care, the lifespan of DMD patients has increased, with many patients now living into their 20s or 30s and some reaching their 40s and 50s   .
Additionally, about 2.5-20% of carriers who were assigned female at birth (with XX chromosomes) may experience some milder DMD symptoms as well . A female carrier who experiences symptoms of DMD is referred to as a “manifesting carrier” and may experience skeletal muscle weakness and cardiac function changes . However, this is rare, and most carriers will experience no issues or symptoms related to DMD .
What do current treatment options look like? Currently, there are five FDA-approved treatments to restore functional dystrophin protein levels, one of them being a gene therapy treatment. Unfortunately, each of these approved drugs treats only a small subset of the DMD patient population. To slow the progression of DMD, patients are often prescribed corticosteroids. Corticosteroids improve muscle strength and function by reducing inflammation and are currently the standard of care for DMD patients . Prednisolone and Emflaza (deflazacourt) are commonly prescribed to DMD patients .
Are there advocacy groups? Yes, there are DMD advocacy groups in the US and worldwide. In the United States, Parent Project Muscular Dystrophy is an organization that works to accelerate relevant research, impact policy, demand optimal care, and access to approved therapies . The Muscular Dystrophy Association is another health organization that advocates for patients and family members of DMD including other muscular dystrophies . Worldwide, there are advocacy groups collected within the global umbrella organization of World Duchenne .
Are there genetic tests? Yes! Prior to genetic testing for DMD, doctors may advise a creatine kinase (CK) blood test . From birth, DMD patients will often have 10-100 times more CK in their bloodstream than that of a healthy patient, due to small tears in their muscle cells causing CK to leak into the bloodstream  . If a patient exhibits high CK levels, they will then be advised to move forward with genetic testing and/or a muscle biopsy . Decode Duchenne offers free genetic testing to individuals in the United States or Canada with a confirmed or suspected diagnosis of Duchenne or Becker muscular dystrophy .
How do scientists and clinicians study this disease?
Are there good/any model systems scientists can use to develop drugs? Different species of animal models have been used to study DMD. The dystrophin-deficient mdx mouse is the most well-studied and common animal model used for DMD . However, this model is disadvantageous because their disease severity does not correlate well with human DMD disease severity . The most favored large animal model for DMD is the canine model, the most widely used being the golden retriever muscular dystrophy dog model which is more similar to human DMD severity in comparison to mdx mice .
Have natural history studies been done? Yes. There is a study that is currently enrolling boys ages 5 to 9 to study the progression of DMD under the current state of care during a period of 6 to 36 months . The largest natural history study on DMD to date has been conducted by the Cooperative International Neuromuscular Research Group (CINRG), enrolling over 500 boys and young men and following their trajectory for up to 10 years from 2006-2016  . This study was influential in planning future clinical trials as well as defining blood biomarkers and genetic polymorphisms .
Certain physicians or centers that are experts? There are many physicians and scientists that are experts on DMD around the world, and some of them are on the Parent Project Muscular Dystrophy scientific advisory committee . For instance, the chair of the committee, Dr. H. Lee Sweeney, is an expert on molecular motors of the myosin superfamily and involved in developing therapeutics for DMD and other muscular atrophies, Translarna being one of them . Dr. Dongsheng Duan, also a member of the PPMD scientific committee, works on developing adeno-associated virus (AAV)-based gene therapy for Duchenne muscular dystrophy and has developed micro-dystrophin vectors to restore functional dystrophin protein in the muscles . Family members of patients in the US are encouraged to look for a certified DMD care center in their area on the Parent Project Muscular Dystrophy website .
What are the major challenges in studying and curing this disease? The DMD gene is very large and thousands of mutations have been identified within the gene of patients with DMD. This presents a vast diversity from patient to patient, making it difficult to develop one drug that would address every DMD patient’s specific needs. Delivery into target tissues, namely muscle, could be improved and new therapeutics conjugated with peptides to improve tissue penetration are currently being evaluated in the clinic . In addition, the large size of the dystrophin gene makes it difficult to package into an AAV for gene therapy approaches .
The Cure Corner: What is needed for a cure?
What does an ideal therapeutic look like? As previously stated, current targeted therapeutic options aim to restore dystrophin levels or lower the rate of muscle tissue deterioration. However, so far the treatments designed to restore dystrophin levels are only amenable to a subset of the population. An ideal therapeutic would reverse the damaging effects to the patient’s muscles and restore the muscle tissue and function that was lost. But for now, the available therapeutic options, such as cortocosteriods, slow the progression of the disease and manage downstream cardiac, respiratory, and other symptoms .
Are there companies already developing drugs? Five drugs have been approved by the FDA to treat DMD and many are currently in clinical trials . Sarepta Therapeutics has developed three FDA-approved drugs: Amondys 45 (casimersen), Exondys 51 (eteplirsen), and Vyondys 53 (golodirsen). These are all therapeutics designed for patients with mutations in the dystrophin gene that are amenable to exon 45, 51, or 53 skipping. A second drug to treat patients with a mutation that is amenable to exon 53 skipping, Viltepso (viltolarsen), was developed by NS Pharma and approved by the FDA in 2020 . Figure 3 shows a schematic of the exon 51 skipping strategy to instruct the body to produce a shorter but functional dystrophin protein. In addition, a gene therapy drug, Elevidys, was approved by the FDA that uses an adeno-associated virus vector to deliver a gene that also leads to a functional, but shortened dystrophin protein being produced by the body  .
There are several other drugs in development. Some of these potential therapies include Pfizer’s gene therapy drug, PF-06939926, currently in Phase 3, NS Pharma’s NS-089/NCNP-02 exon 44 skipping drug (Phase 2), and Sarepta Therapeutics’ exon 51 skipping drug, SRP-5051 (Phase 2)   . About 13% of DMD patients have a mutation amenable to Exon 51 skipping, and Exondys 51 (eteplirsen) was designed to fit this need but Sarepta’s new drug, P-5051, could be dosed less frequently if it proves more efficacious . Exon skipping of exon 44 can be effective for 12% of DMD patients .
What are current therapies and treatments lacking? Currently, the five FDA-approved therapies each only treat a small subset of the DMD patient population because of age restrictions and/or specific mutations being targeted. For example, there are two drugs available for patients who have a mutation amenable to exon 53 skipping, but this covers only approximately 8% of DMD patients , and similarly, Exondys 51 (eteplersen) can be used to treat only 14% of DMD cases . Due to the diversity of mutations in the dystrophin gene across the DMD patient population, these strategies can be limiting.
Could an RNA therapeutic fit the need? Currently, there are four FDA-approved therapeutics that are exon-skipping antisense oligonucleotide drugs, and many more are in development or in clinical trials. Improving the efficacy and potency of these drugs is on-going, for example, through the conjugation of peptides to improve tissue penetration . However, as previously stated, each of these approved drugs only applies to a small percentage of the population. High variation in mutations in the dystrophin gene among DMD patients might necessitate for personalized therapy with antisense therapeutics.
DMD is a progressive and devastating neuromuscular disease affecting mostly young males. Although progress has been made in developing therapeutics to treat the underlying causes of DMD, including five FDA-approved therapies and more globally, there is still an unmet need to treat all DMD patients effectively. A strong DMD advocacy community continues pushing for federal research funding and keeps us hopeful for a future treatment.
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