When I was diagnosed with Muscular Dystrophy in first grade, I was six or seven years old and had no idea what it was or even that I had it in the first place. As I grew older I slowly learned more about what I had, how I was different because of it, and how the disease worked. I got more involved with Muscular Dystrophy over time and, through watching the MDA Labor Day Telethon, I learned of a new treatment option being explored from a video similar to this one. This new treatment is called Exon Skipping. I recently became more interested in the subject so I decided to blog about it. When I was doing my research, I asked three questions about Exon Skipping. First, more for your (the reader’s) information than mine, I asked “What is Muscular Dystrophy?” I also asked two other questions. How does Muscular Dystrophy affect genes and the exons and introns that make up genes? How does exon skipping work?
The first important question I decided to research was what Muscular Dystrophy is exactly. Through the years I have done many projects that have to do with Muscular Dystrophy so I asked this question to inform the reader. Muscular Dystrophy is a group of genetic conditions in which muscles become weak and wasted. Muscular Dystrophy is a relatively common genetic disease which affects mainly boys. There are two main types of Muscular Dystrophy, Duchenne and Becker. Duchenne Muscular Dystrophy affects about one in 4,000 boys in the United States and the less severe, rarer Becker Muscular Dystrophy affect about one in every 25,000 boys. Muscular Dystrophy is caused be an abnormal gene carried on the X sex chromosome. Since girls have two X chromosomes, they may carry the disease but rarely show symptoms because they have another chromosome to pick up the slack of the defective chromosome. Boys only have one X chromosome which means that if a boy has the defective chromosome, they will show the symptoms of the disease. Within these chromosomes is the gene that creates dystrophin, a protein that is necessary for healthy muscles. Without this protein, the muscles gradually lose strength and begin to get damaged. In boys with Duchenne Muscular Dystrophy, the gene that creates dystrophin is abnormal and no dystrophin is produced. In Becker Muscular Dystrophy, some dystrophin is created, explaining the difference in severity from Duchenne to Becker. The symptoms of Duchenne Muscular Dystrophy are normally not noticed until the child begins to walk, which generally happens later than in other children. Children with Duchenne Muscular Dystrophy also fall more often than other children. Although these are symptoms, the more obvious ones appear closer to the ages of 3 to 5 years. Among these symptoms are difficulty climbing stairs and getting up from the floor, large calf muscles, and wasted muscle at the tops of the legs and arms. These symptoms are progressive and end up forcing the child into a wheelchair because of the inability to walk at about age 12. The symptoms of Becker Muscular Dystrophy are similar but are normally not seen until age 11 or even later because of its slower progression. There are many muscle related complications that can occur with this disease, usually getting worse once the child is wheelchair bound. There are tests that can be done to determine if a child has Muscular Dystrophy including blood tests and muscle biopsies, which is when a sample of the muscle is taken and examined under a microscope. Currently, the main goals for treatment of this disease are keeping the child active as long as possible. Physical therapy is used and surgery may be required to straighten a child spine due to scoliosis. Patients with Muscular Dystrophy normally have a shorter life than people without the disease due to the complications that can occur with muscles including the heart and respiratory system. Now that you have an adequate amount of information on Muscular Dystrophy, I will go into how Muscular Dystrophy affects genes which leads into Exon Skipping.
The second question I decided to cover was “How does Muscular Dystrophy affect genes and the exons and introns that make up genes?” To start, a gene is a section of DNA that contains the instructions for the production of one specific protein. Within these genes are sections called exons and introns. The introns are not important here, but the exons code for the protein. The dystrophin gene is the largest gene in the human genome, making it incredibly vulnerable to mutation and resulting in different cases for almost every patient. Although this is true, there are certain areas that are affected more often than other areas. The dystrophin gene also has 79 exons which connect like a puzzle. In Becker Muscular Dystrophy, an exon is deleted, but the two around it can still join together. This results in a shortened gene that still creates dystrophin, but it is not quite as strong as dystrophin from a person without Muscular Dystrophy. Now, in Duchenne Muscular Dystrophy this is more serious. In this type of Muscular Dystrophy exons are deleted and end up interfering with the rest of the gene. The exons around the one that gets deleted cannot join together, which results in a non-functional dystrophin protein and the symptoms of Duchenne Muscular Dystrophy. This is when exon skipping comes into play.
The last and most important question I researched was “How does exon skipping work?” This therapy works by encouraging the cellular machinery to ‘skip over’ an exon with the use of ‘molecular patches’ which are small pieces of DNA called antisense oligonucleotides. These patches are used to mask the exon that you want to skip, ignoring the exon during protein production and resulting in dystrophin similar to the kind created in Becker Muscular Dystrophy. This results in symptoms more like Beckers Muscular Dystrophy rather than Duchenne. This has been effective in mouse models and in human Duchenne Muscular Dystrophy muscle cells grown in a lab. There have also been studies with humans, in which the molecular patch is injected into the bloodstream or under the skin. The drugs that are tested normally target exon 51, an exon that is considered a hot spot as 13% of Duchenne Muscular Dystrophy patients carry a mutation on this exon. In one study, 19 boys aged 5 to 15, with mutations in the exon 51 region, were recruited and given varying doses of the exon-skipping therapy. Seven of the trial participants showed restoration in the dystrophin protein ranging from 18% to 50% of the dystrophin levels found in most people. In different studies, patients that were injected with the highest doses of this therapy had significant dystrophin regeneration with no clear negative effects. In the future, there could be extended administration and increased doses, but this depends on safety. With the correct administration and doses, this therapy could improve muscle function significantly. Although these patches are not a cure, they can make the symptoms of Duchenne Muscular Dystrophy less severe and more like Becker Muscular Dystrophy. This is shown with pictures and explained more extensively on the website here.
Duchenne Muscular Dystrophy is a severe disease that affects more boys than any other genetic disease, but this new therapy could result in a better prognosis for every boy with this devastating disease. The chances of this disease occurring in a boy are relatively high compared to other genetic diseases and can make life difficult with wheelchairs and other assistive devices like leg braces. With this exon skipping therapy available, it would make the life of these boys easier and better as a whole.
Are there other treatment options used to treat Muscular Dystrophy? Is this therapy only used for Duchenne Muscular Dystrophy or is it used for the multiple other types of Muscular Dystrophy? Will the same therapy type work for all patients with Duchenne Muscular Dystrophy?