Another Muscular Dystrophy Mystery Solved; Scientists Inch Closer to a Therapy for Patients
ScienceDaily (Dec. 7, 2012) — Approximately 250,000 people in the United States suffer from muscular dystrophy, which occurs when damaged muscle tissue is replaced with fibrous, bony or fatty tissue and loses function.
Three years ago, University of Missouri scientists found a molecular compound that is vital to curing the disease, but they didn’t know how to make the compound bind to the muscle cells. In a new study, published in the Proceedings of the National Academies of Science, MU School of Medicine scientists Yi Lai and Dongsheng Duan have discovered the missing pieces to this puzzle that could ultimately lead to a therapy and, potentially, a longer lifespan for patients suffering from the disease.
Duchenne muscular dystrophy (DMD), predominantly affecting males, is the most common type of muscular dystrophy. Patients with Duchenne muscular dystrophy have a gene mutation that disrupts the production of dystrophin, a protein essential for muscle cell survival and function. Absence of dystrophin starts a chain reaction that eventually leads to muscle cell degeneration and death. While dystrophin is vital for muscle development, the protein also needs several “helpers” to maintain the muscle tissue. One of these “helper” molecular compounds is nNOS, which produces nitric oxide that can keep muscle cells healthy after exercise.
“Dystrophin not only helps build muscle cells, it’s also a key factor to attracting nNOS to the muscles cells and helping nNOS bind to the cell and help repair it following activity,” said Lai, a research assistant professor in the Department of Molecular Microbiology and Immunology. “Prior to this discovery, we didn’t know how dystrophin made nNOS bind to the cells. What we found was that dystrophin has a special ‘claw’ that is used to grab nNOS and bring it close to the muscle cell. Now that we have that key, we hope to begin the process of developing a therapy for patients.”
In their study, Lai and Duan found that two particular sections of the dystrophin gene must be present for nNOS to bind to the muscle cells. The sections of the gene, known as “repeaters 16 & 17,” contain a “claw” that can grab nNOS and bring it to the muscle cells so that it will bind and repair any damage from regular use. Without this “claw,” nNOS doesn’t bind to the cells and the damage is not repaired, leading to further problems associated with muscular dystrophy.
The other key to this puzzle is dystrophin. If the protein is not present in the body, no “claw” exists and nNOS would never make it to the muscle cells. For years, scientists have been attempting to find ways to make the body manufacture more dystrophin, and thus get more nNOS to the muscle cells. Duan and Lai said the answer might lie elsewhere.
“Everybody, including those individuals with muscular dystrophy, has another protein known as ‘utrophin,'” said Duan, a professor of molecular microbiology and immunology. “Utrophin is nearly identical to dystrophin except that it is missing repeaters 16 & 17, so it cannot attract nNOS to the muscle cells. In our study, we were able to modify utrophin so that it had the repeaters, and thus, the ability to grab nNOS and bring it to the muscle cells for repair. Our study was completed in mice; if we can do the same thing in larger animals, we could eventually have a significant therapy for humans with this devastating disease.”
The early-stage results of this research are promising. If additional studies, including large animal studies, are successful within the next few years, MU officials will request authority from the federal government to begin human drug development (this is commonly referred to as the “investigative new drug” status). After this status has been granted, researchers may conduct human clinical trials with the hope of developing new treatments for the disease.
Muscular Dystrophy and Autism – Harvard 2012
Co-morbid Conditions and Autism – Harvard Medical
Gene Therapy Reveals Unexpected Immunity To Dystrophin In Patients With Duchenne Muscular Dystrophy
Natural immunity to dystrophin may contribute to muscle disease and complicate experimental therapies
An immune reaction to dystrophin, the muscle protein that is defective in patients with Duchenne muscular dystrophy, may pose a new challenge to strengthening muscles of patients with this disease, suggests a new study appearing in the October 7, 2010, issue of The New England Journal of Medicine.
“With one safety trial involving six patients, Drs. Mendell and Walker have provided a tremendous service to scientists advancing gene therapy research – particularly for muscular dystrophy,” said Louis M. Kunkel, Ph.D., chairman of the MDA Scientific Advisory Committee. “By uncovering a somewhat surprising T cell immune response to dystrophin, they’re helping investigators refine several distinct and promising approaches to treating Duchenne muscular dystrophy (DMD) by correcting or adding the dystrophin protein that is defective in the disease.”
To understand why this therapy failed, the researchers measured immune responses against dystrophin. “We were concerned about immunity caused by a certain type of white blood cell called the T lymphocyte. The natural role of T cells is to protect us from infection and cancer by destroying cells that are recognized as different or foreign,” said Christopher M. Walker, PhD, director, Center for Vaccines and Immunity at The Research Institute and one of the study authors. “Parts of the corrected dystrophin protein are clearly foreign because of the patient’s DMD gene deletion, and so unwanted T cell immunity targeting the repaired muscle cells was a possibility.”
The researchers did detect T cell immunity was against foreign segments of the corrected dystrophin protein in one patient with a large DMD gene deletion. However, stronger and faster T cell immunity was detected in a second patient with a much smaller DMD gene deletion.
“Strong, rapid immunity in the second patient with a very small DMD gene deletion was a surprise,” said Dr. Walker. “The amount of corrected dystrophin protein that is foreign should also be small, and possibly ignored altogether by the T cells.”
The mystery deepened further when T cell immunity to dystrophin was found to have been present in this patient even before treatment. Careful examination of the muscle revealed that the T cells present before gene therapy recognized dystrophin that is produced in a very small percentage of muscle cells that naturally self-correct the defective DMD gene. Delivery of the gene therapy vector to biceps muscle boosted and accelerated this pre-existing immune response.
Central nervous system involvements in Duchenne/Becker muscular dystrophy.
Aichi Welfare Center for Persons with Developmental Disabilities, Kasugai, Aichi.
Duchenne/Becker muscular dystrophy (DMD/BMD) are the most common inherited muscular diseases caused by mutations in the dystrophin gene.
The identification of novel dystrophins in the brain has recently implicated its absence or malfunction etiologically in mental retardation (MR).
We therefore examined the relationship between molecular abnormalities and clinical phenotypes.
Deletions of the dystrophin gene were analyzed in a total of 137 DMD/BMD patients (DMD 94, BMD 43) to determine central nervous system (CNS) symptoms.
The mental capacity was assessed and patients with IQs below 70 were defined as mentally retarded. Thirty-nine percent of DMD boys and 12% of BMD patients were classified as mentally retarded.
Eight DMD and 2 BMD patients were diagnosed as having autism.
Forty-four percent of DMD and 79% of BMD patients had deletions in the dystrophin gene.
All the DMD/BMD patients with deletions upstream of the 5′ end of the gene were mentally normal.
All of DMD/BMD patients with MR and/or autism had deletions containing the 3′ end, although some patients with similar deletions were mentally normal.
Our data suggest that Dp140, Dp71 and/or Dp116, the C-terminal translational products of dystrophin, may be related to MR and/or autism in DMD/BMD.
However, there was an exception in our series. Three of eight sibling pairs in our cases had different phenotypes, although they had the same mutations in the dystrophin gene. Thus the CNS phenotypes were not determined by the mutations of dystrophin gene alone, and the interaction of dystrophin with other nuclear genes may play important roles.