Finally, for some MDs, early detection of the disease causing mutations, through newborn screening, may be necessary for gene replacement therapy to be used early enough to mitigate progression of the disease.
Clinical testing of gene therapy strategies in MD has been underway for Duchenne and limb girdle muscular dystrophy. Injections of gene therapy vectors into single muscles of participants were done as a first step to establish safety of the approach.
With the support of extensive studies in animal models, clinical trials are now moving toward testing of gene therapy of all muscles of entire limbs, using an isolated vascular delivery approach. If isolated limb delivery approaches prove safe and effective, research will move to systemic delivery of gene therapy vectors so all muscles can be treated simultaneously.
Utrophin is a protein that is closely related to dystrophin and is not affected in the gene mutations that cause Duchenne MD.
Targeting increased expression of utrophin may prove a useful approach in treating Duchenne MD. NIH supports both gene therapy and small molecule drug development programs to increase the muscle production of utrophin. These genes, including latent TGF binding protein 4 and osteopontin, represent new therapeutic targets to potentially reduce the severity of several types of muscular dystrophy.
Genetic modification therapy to bypass inherited mutations Most individuals with Duchenne have mutations in the dystrophin gene that cause it to function improperly and stop producing the dystrophin protein. This strategy, which is potentially useful in about 15 percent of individuals with Duchenne MD, is currently in clinical trials. Second, a more recent approach uses antisense oligonucleotides short strands of nucleic acid designed to block the transfer of some genetic information into protein production to alter splicing and produce nearly a full-length dystrophin gene, potentially converting an individual with Duchenne to a much milder Becker MD.
An exon is a coding sequence in a gene for a protein. Antisense oligonucleotide technology is also being evaluated for use in myotonic dystrophy, but by a different mechanism than in Duchenne MD.
In myotonic dystrophy, long duplications of repetitive DNA sequences lead to production of a toxic RNA that sequesters a splicing regulator, Muscleblind, causing mis-splicing of many genes in muscle and brain.
This approach, in partnership with academic investigators and biotechnology and pharmaceutical companies, has the potential to address all people having myotonic dystrophy and is planned to be in clinical trials within the next few years.
Drug-based therapy to delay muscle wasting by promoting muscle growth or mitigating damage due to inflammation Progressive loss of muscle mass is primarily responsible for reduced quality and length of life in MD.
Drug treatment strategies designed to slow this muscle degeneration can have substantial impact on quality of life. Similarly, skeletal muscle has the ability to repair itself, but its regeneration and repair mechanisms are progressively depleted during the course of several types of MD. Understanding the repair mechanisms may provide new therapies to slow, and possibly stabilize, muscle degeneration. Corticosteroids are known to extend the ability of people with Duchenne MD to walk by up to 2 years, but steroids have substantial side effects and their mechanism of action is unknown.
Since several corticosteroid protocols are used, an NINDS-funded study is evaluating drugs and their efficacy and tolerability at different doses in order to determine optimal clinical practice for their use in Duchenne MD.
Preclinical drug development efforts supported by NINDS and NIAMS are developing a peptide therapeutic that has, in animal models, dual activity in mitigating muscle damage due to inflammation and also enhancing muscle regeneration. Efforts to preserve muscle mass through inhibition of a negative regulator of muscle growth, myostatin, have encountered some roadblocks, including failed clinical trials, but are still under study.
Cell-based therapy The muscle cells of people with MD often lack a critical protein, such as dystrophin in Duchenne MD or sarcoglycan in some of the limb-girdle MDs. Scientists are exploring the possibility that the missing protein can be replaced by introducing muscle stem cells capable of making the missing protein in new muscle cells. Such new cells would be protected from the progressive degeneration characteristic of MD and potentially restore muscle function in affected persons.
The natural regenerative capacity of muscle provides possibilities for treatment of MD. Researchers have shown that stem cells can be used to deliver a functional dystrophin gene to skeletal muscles of dystrophic mice and dogs. The focus of research has been on identifying the cell types with the highest potential for engraftment and growth of muscle and on strategies to deliver these muscle precursor cells to human skeletal muscles.
Overall, cell-based therapeutic approaches are under consideration for multiple types of MD. With the dramatic advances in understanding disease mechanisms, significant therapy development efforts are now being launched in many types of MD. NINDS funding supports teams working on the disease mechanisms in facioscapulohumeral muscular dystrophy, central nervous system involvement in myotonic dystrophy, and on the role of fibrosis in Duchenne MD.
Importantly, parallel efforts need to be made in clinical trial readiness, so that clinical trials are feasible when a candidate therapeutic reaches that stage. Patient registries, natural history studies, biomarker identification, development of clinical trial endpoint measures, and emergence of standards of care are all essential in supporting clinical trials and are being advanced in several types of muscular dystrophy with the support of both public and private sector partners.
The NIH has recently undertaken several new initiatives in training, career development, and research that are targeted toward MD.
These advances, along with the NINDS focus on translational and clinical research, will lead to the growth of clinical trials and promising treatment strategies. The MD Coordinating Committee is made up of physicians, scientists, NIH professional staff, and representatives of other federal agencies and voluntary health organizations with a focus on MD.
The purpose of the group is to help NIH add new capabilities to the national effort to understand and treat MD, without duplicating existing programs.
The MD Coordinating Committee has developed a broad Action Plan for the Muscular Dystrophies and continues to refine the plan to improve basic, translational, and clinical research in MD, with the goal of improving the quality of life for people with MD. Information about the committee and plan is available at https: The Act also authorized the Centers for Disease Control and Prevention to award grants for epidemiologic studies, data collection, and development of standards of care for several types of MD.
Other federal agencies contribute to this research initiative. Research has led to the discovery of disease mechanisms and improved treatment for many forms of MD. Current research promises to generate further improvements. In the coming years, physicians and affected individuals can look forward to new forms of therapy developed through an understanding of the unique traits of MD.
Box Bethesda, MD http: Box Olathe, KS info curecmd. NINDS health-related material is provided for information purposes only and does not necessarily represent endorsement by or an official position of the National Institute of Neurological Disorders and Stroke or any other Federal agency.
Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient's medical history. Skip to main content. Enter Search Term Submit Search. Table of Contents click to jump to sections Introduction What is muscular dystrophy?
Glossary Introduction The first historical account of muscular dystrophy appeared in , when Sir Charles Bell wrote an essay about an illness that caused progressive weakness in boys. What is muscular dystrophy? Muscular dystrophies can be inherited in three ways: Autosomal means the genetic mutation can occur on any of the 22 non-sex chromosomes in each of the body's cells.
Dominant means only one parent needs to pass along the abnormal gene in order to produce the disorder. In families where one parent carries a defective gene, each child has a 50 percent chance of inheriting the gene and therefore the disorder. Males and females are equally at risk and the severity of the disorder can differ from person to person.
The parents each have one defective gene but are not affected by the disorder. Children of either sex can be affected by this pattern of inheritance. Sons of carrier mothers have a 50 percent chance of inheriting the disorder.
Daughters also have a 50 percent chance of inheriting the defective gene but usually are not affected, since the healthy X chromosome they receive from their father can offset the faulty one received from their mother. Affected fathers cannot pass an X-linked disorder to their sons but their daughters will be carriers of that disorder.
Carrier females occasionally can exhibit milder symptoms of MD. There are three groups of congenital MD: Defects in the protein merosin cause nearly half of all cases of congenital MD. Various laboratory tests may be used to confirm the diagnosis of MD. Creatine kinase is an enzyme that leaks out of damaged muscle. Elevated creatine kinase levels may indicate muscle damage, including some forms of MD, before physical symptoms become apparent.
Levels are significantly increased in the early stages of Duchenne and Becker MD. Testing can also determine if a young woman is a carrier of the disorder. The level of serum aldolase, an enzyme involved in the breakdown of glucose, is measured to confirm a diagnosis of skeletal muscle disease. High levels of the enzyme, which is present in most body tissues, are noted in people with MD and some forms of myopathy. Myoglobin is an oxygen-binding protein found in cardiac and skeletal muscle cells.
High blood levels of myoglobin are found in people with MD. Polymerase chain reaction PCR can detect some mutations in the dystrophin gene. Also known as molecular diagnosis or genetic testing, PCR is a method for generating and analyzing multiple copies of a fragment of DNA. Serum electrophoresis is a test to determine quantities of various proteins in a person's DNA.
A blood sample is placed on specially treated paper and exposed to an electric current. The charge forces the different proteins to form bands that indicate the relative proportion of each protein fragment.
Amniocentesis, done usually at weeks of pregnancy, tests a sample of the amniotic fluid in the womb for genetic defects the fluid and the fetus have the same DNA. Under local anesthesia, a thin needle is inserted through the woman's abdomen and into the womb. About 20 milliliters of fluid roughly 4 teaspoons is withdrawn and sent to a lab for evaluation. Test results often take weeks. Chorionic villus sampling, or CVS, involves the removal and testing of a very small sample of the placenta during early pregnancy.
The sample, which contains the same DNA as the fetus, is removed by catheter or a fine needle inserted through the cervix or by a fine needle inserted through the abdomen. The tissue is tested for genetic changes identified in an affected family member. Results are usually available within 2 weeks. Nerve conduction velocity studies measure the speed and strength with which an electrical signal travels along a nerve.
A small surface electrode stimulates a nerve, and a recording electrode detects the resulting electrical signal either elsewhere on the same nerve or on a muscle controlled by that nerve.
The response can be assessed to determine whether nerve damage is present. Repetitive stimulation studies involve electrically stimulating a motor nerve several times in a row to assess the function of the neuromuscular junction. The recording electrode is placed on a muscle controlled by the stimulated nerve, as is done for a routine motor nerve conduction study. A tiny needle containing an electrode is inserted through the skin into the muscle.
The electrical activity detected in the muscle can be displayed on a monitor, and can also be heard when played through a speaker. Results may reveal electrical activity characteristic of MD or other neuromuscular disorders. Passive stretching can increase joint flexibility and prevent contractures that restrict movement and cause loss of function. When done correctly, passive stretching is not painful. The therapist or other trained health professional slowly moves the joint as far as possible and maintains the position for about 30 seconds.
The movement is repeated several times during the session. Passive stretching on children may be easier following a warm bath or shower. Regular, moderate exercise can help people with MD maintain range of motion and muscle strength, prevent muscle atrophy, and delay the development of contractures.
Individuals with a weakened diaphragm can learn coughing and deep breathing exercises that are designed to keep the lungs fully expanded. Postural correction is used to counter the muscle weakness, contractures, and spinal irregularities that force individuals with MD into uncomfortable positions.
When possible, individuals should sit upright, with feet at a degree angle to the floor. Pillows and foam wedges can help keep the person upright, distribute weight evenly, and cause the legs to straighten. Armrests should be at the proper height to provide support and prevent leaning. Support aids such as wheelchairs, splints and braces, other orthopedic appliances, and overhead bed bars trapezes can help maintain mobility.
Braces are used to help stretch muscles and provide support while keeping the person ambulatory. Spinal supports can help delay scoliosis. Night splints, when used in conjunction with passive stretching, can delay contractures. Orthotic devices such as standing frames and swivel walkers help people remain standing or walking for as long as possible, which promotes better circulation and improves calcium retention in bones.
Repeated low-frequency bursts of electrical stimulation to the thigh muscles may produce a slight increase in strength in some boys with Duchenne MD, though this therapy has not been proven to be effective. Tendon or muscle-release surgery is recommended when a contracture becomes severe enough to lock a joint or greatly impair movement. The procedure, which involves lengthening a tendon or muscle to free movement, is usually performed under general anesthesia.
Rehabilitation includes the use of braces and physical therapy to strengthen muscles and maintain the restored range of motion. A period of immobility is often needed after these orthopedic procedures, thus the benefits of the procedure should be weighed against the risk of this period of immobility, as the latter may lead to a setback. Individuals with either Emery-Dreifuss or myotonic dystrophy may require a pacemaker at some point to treat cardiac problems.
Surgery to reduce the pain and postural imbalance caused by scoliosis may help some individuals. Scoliosis occurs when the muscles that support the spine begin to weaken and can no longer keep the spine straight.
The spinal curve, if too great, can interfere with breathing and posture, causing pain. One or more metal rods may need to be attached to the spine to increase strength and improve posture. Chronic inflammation leads to fibrosis and reduced muscle regeneration.
Cardiac failure is the leading cause of death with those of Duchenne. DMD-associated dilated cardiomyopathy is a form of cardiac failure that is caused by mutations in the DMD gene. Dilated cardiomyopathy enlarges and weakens the cardiac muscle, preventing the heart from pumping blood efficiently.
Two components are necessary for the system to work: This technology has the potential to permanently correct the faulty DNA present in a Duchenne patient. Researchers are investigating many details about satellite cells and the causes of muscle damage as well as treatments that help reduce muscle damage, such as anti-inflammatory treatments.
Studies are examining ways to preserve, and possibly restore, muscle function by transplanting dystrophin-producing cells into patients. Induced pluripotent stem cells iPSCs are being studied as an option for making large numbers of cells with healthy dystrophin genes. Treating patients with their own cells either genetically modified cells or iPSCs can largely overcome transplant rejection but have other risks.
Another major challenge is engraftment: Evenly distributing cells to muscles throughout the body is a big challenge for cell therapy treatment. Muscular dystrophies are a group of genetic diseases that affect skeletal muscles and often also heart muscle. The symptoms include muscle weakness and progressive muscle wasting. Duchenne muscular dystrophy DMD is the most common and a very severe form of the disease. It is caused by a genetic fault which prevents the production of a protein called dystrophin.
Without dystrophin, muscles are fragile and are easily damaged. The majority of a muscle is formed from bundles of muscle fibres, long cells containing many nuclei; but muscles also contain many other types of cells, including stem cells.
They can generate progenitor cells and also make copies of themselves. Skeletal muscles contain a type of stem cell called satellite cells. When muscle fibres are damaged they send chemical signals to satellite cells telling them to form new muscle fibres or to fuse with existing fibres to repair the damage. At the same time some satellite cells copy themselves to ensure enough stem cells are available to continue to repair and replace muscle fibres in the future. Scientists believe that because the muscles are constantly damaged in DMD the repair burden placed on satellite cells is so big that they become exhausted and lose their ability to copy themselves.
Satellite cells are essential for muscle repair so as the number of these cells decreases, the muscle becomes less and less able to repair itself. Instead damaged muscle fibres are replaced by fat cells and scar tissue, weakening the muscle until it can no longer work effectively.
Currently there is no definitive cure for DMD. Steroids are routinely used to slow down muscle wasting but they have many side effects, including weakening of bones leading to osteoporosis, hypertension and delayed growth. Physiotherapy may partially help to maintain muscle strength and flexibility. Researchers are hoping that, in the future, they may be able to repair or replace damaged muscle fibres using different strategies, including transplantation of dystrophin-producing cells to restore or at least preserve muscle function.
There are a number of different types of stem cells that scientists think may be used in different ways to develop treatments for muscular dystrophy. The main stem-cell-based approaches currently being investigated are:. Beside stem cells, other therapeutic strategies such as gene therapy or small-molecule drugs for repairing the damaged gene are being tested in patients and in pre-clinical models. Future therapies are likely to use a combination of more than one of these approaches.
Scientists are also studying the role of stem cells in the maintenance and repair of healthy muscles in order to understand in more detail what goes wrong in muscular dystrophy and how the problem could be corrected. Much current research is focussed on developing ways to restore production of the missing protein dystrophin in the muscles of DMD patients. Myoblasts Myoblasts are a type of cell formed from satellite cells after birth. Myoblasts fuse together to form muscle fibres. When injected into the muscles of mice with muscle damage similar to that caused by DMD, myoblasts from healthy donor mice fuse with the diseased muscle fibres and partially restore dystrophin production.
Scientists around the globe are conducting intense research to understand what causes muscle dysfunction in Duchenne muscular dystrophy (DMD) and to apply that understanding to the development of effective treatments.
Current Research The cornerstone of Parent Project Muscular Dystrophy’s mission is to identify and support promising Duchenne muscular dystrophy research that can impact all those living with Duchenne now, during their lifetime. No one in.
Sep 08, · Read about the promise of stem cell research for muscular dystrophy patients, and successful treatments tested in dogs. Your source for the latest research news Follow Subscribe. Breaking news in research. from this trial encouraged the Committee for Medicinal Products for Human Use to recommend the expansion of the drug’s current licence to include boys as young as two. (FDA) has granted Orphan Drug Designation to GBC for the treatment of facioscapulohumeral muscular dystrophy.
Aug 09, · "Muscular Dystrophy: Hope Through Research", NINDS, Publication date August NIH Publication No. Back to Muscular Dystrophy Information Page See . Cedars-Sinai's muscular dystrophy research is multidisciplinary. Researchers collaborate with the Baloh Laboratory, the Institute of Genetic and Molecular Medicine in the United Kingdom, the University of Florida's Powell Gene Therapy Center, UCLA's Department of Biomathematics and the Center for Duchenne Muscular Dystrophy at UCLA.