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Muscular dystrophies (MD) are a genetically and clinically heterogeneous group of rare neuromuscular diseases that cause progressive weakness and breakdown of skeletal muscles over time. The disorders differ as to which muscles are primarily affected, the degree of weakness, how fast they worsen, and when symptoms begin. Some types are also associated with problems in other organs.
Dystrophin is a rod-shaped cytoplasmic protein, and a vital part of a protein complex that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through the cell membrane. This complex is variously known as the costamere or the dystrophin-associated protein complex (DAPC). Many muscle proteins, such as α-dystrobrevin, syncoilin, synemin, sarcoglycan, dystroglycan, and sarcospan, colocalize with dystrophin at the costamere. It has a molecular weight of 427 kDa
Duchenne muscular dystrophy (DMD) is a severe type of muscular dystrophy that primarily affects boys. Muscle weakness usually begins around the age of four, and worsens quickly. Muscle loss typically occurs first in the thighs and pelvis followed by the arms. This can result in trouble standing up. Most are unable to walk by the age of 12. Affected muscles may look larger due to increased fat content. Scoliosis is also common. Some may have intellectual disability. Females with a single copy of the defective gene may show mild symptoms.
Becker muscular dystrophy is an X-linked recessive inherited disorder characterized by slowly progressing muscle weakness of the legs and pelvis. It is a type of dystrophinopathy. This is caused by mutations in the dystrophin gene, which encodes the protein dystrophin. Becker muscular dystrophy is related to Duchenne muscular dystrophy in that both result from a mutation in the dystrophin gene, but has a milder course.
The dystrophin-associated protein complex, also known as the dystrophin-associated glycoprotein complex is a multiprotein complex that includes dystrophin and the dystrophin-associated proteins. It is one of the two protein complexes that make up the costamere in striated muscle cells. The other complex is the integrin-vinculin-talin complex.
Utrophin is a protein that in humans is encoded by the UTRN gene. The name is a short form for ubiquitous dystrophin.
Dame Kay Elizabeth Davies is a British geneticist. She is Dr Lee's Professor of Anatomy at the University of Oxford and a Fellow of Hertford College, Oxford. She is director of the Medical Research Council (MRC) functional genetics unit, a governor of the Wellcome Trust, a director of the Oxford Centre for Gene Function, and a patron and Senior Member of Oxford University Scientific Society. Her research group has an international reputation for work on Duchenne muscular dystrophy (DMD). In the 1980s, she developed a test which allowed for the screening of foetuses whose mothers have a high risk of carrying DMD.
Originally identified as Kirsten ras associated gene (KRAG), sarcospan (SSPN) is a 25-kDa transmembrane protein located in the dystrophin-associated protein complex of skeletal muscle cells, where it is most abundant. It contains four transmembrane spanning helices with both N- and C-terminal domains located intracellularly. Loss of SSPN expression occurs in patients with Duchenne muscular dystrophy. Dystrophin is required for proper localization of SSPN. SSPN is also an essential regulator of Akt signaling pathways. Without SSPN, Akt signaling pathways will be hindered and muscle regeneration will not occur.
Dystrobrevin is a protein that binds to dystrophin in the costamere of skeletal muscle cells. In humans, there are at least two isoforms of dystrobrevin, dystrobrevin alpha and dystrobrevin beta.
Alpha-sarcoglycan is a protein that in humans is encoded by the SGCA gene.
Dystrobrevin alpha is a protein that in humans is encoded by the DTNA gene.
Sarcoglycan zeta also known as SGCZ is a protein which in humans is encoded by the SGCZ gene.
In molecular biology, exon skipping is a form of RNA splicing used to cause cells to “skip” over faulty or misaligned sections (exons) of genetic code, leading to a truncated but still functional protein despite the genetic mutation.
Ezutromid is an orally administered small molecule utrophin modulator involved in a Phase 2 clinical trial produced by Summit Therapeutics for the treatment of Duchenne muscular dystrophy (DMD). DMD is a fatal x-linked recessive disease affecting approximately 1 in 5000 males and is a designated orphan disease by the FDA and European Medicines Agency. Approximately 1/3 of the children obtain DMD as a result of spontaneous mutation in the dystrophin gene and have no family history of the disease. Dystrophin is a vital component of mature muscle function, and therefore DMD patients have multifarious forms of defunct or deficient dystrophin proteins that all manifest symptomatically as muscle necrosis and eventually organ failure. Ezutromid is theorized to maintain utrophin, a protein functionally and structurally similar to dystrophin that precedes and is replaced by dystrophin during development. Utrophin and dystrophin are reciprocally expressed, and are found in different locations in a mature muscle cell. However, in dystrophin-deficient patients, utrophin was found to be upregulated and is theorized to replace dystrophin in order to maintain muscle fibers. Ezutromid is projected to have the potential to treat all patients suffering with DMD as it maintains the production of utrophin to counteract the lack of dystrophin to retard muscle degeneration. Both the FDA and European Medicines Agency has given ezutromid an orphan drug designation. The FDA Office of Orphan Products and Development offers an Orphan Drug Designation program (ODD) that allows drugs aimed to treat diseases that affect less than 200,000 people in the U.S. monetary incentives such as a period of market exclusivity, tax incentives, and expedited approval processes.
H. Lee Sweeney is an American scientist who studies muscle.
Anne McArdle is a physiologist at the University of Liverpool.
Dystrophinopathy refers to a spectrum of diseases due to mutations in the DMD gene, which encodes for the dystrophin protein found in muscle. The severe end of the spectrum includes Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and DMD-associated dilated cardiomyopathy. The mild end of the spectrum includes asymptomatic increases in serum creatine kinase and muscle cramps with myoglobinuria. Because dystrophin is located on the X chromosome, dystrophinopathy mainly affects males, whereas females range from being carriers, to having delayed-onset and mild disease, to having severe DMD.
Viltolarsen, sold under the brand name Viltepso, is a medication used for the treatment of Duchenne muscular dystrophy (DMD). Viltolarsen is a Morpholino antisense oligonucleotide.
Toshifumi (Toshi) Yokota is a medical scientist and professor of medical genetics at the University of Alberta, where he also holds the titles of the Friends of Garrett Cumming Research & Muscular Dystrophy Canada Endowed Research Chair and the Henri M. Toupin Chair in Neurological Science. He is best known for his studies of antisense oligonucleotide-based therapeutics for muscular dystrophy that led to the development of an FDA-approved drug viltolarsen. His research interests include precision medicine for muscular dystrophy and genetic diseases. He has co-edited two books both published in the Methods in Molecular Biology series from Humana Press, Springer-Nature, and has published more than 100 refereed papers and patents. He is a member of the editorial boards for the International Journal of Molecular Sciences, Genes, Frontiers in Genome Editing, Frontiers in Physiology, and Nucleic Acid Therapeutics, a member of the Medical and Scientific Advisory Committee of Muscular Dystrophy Canada, and a co-founder of the Canadian Neuromuscular Network (CAN-NMD).
Casimersen, sold under the brand name Amondys 45, is an antisense oligonucleotide medication used for the treatment of Duchenne muscular dystrophy (DMD) in people who have a confirmed mutation of the dystrophin gene that is amenable to exon 45 skipping. It is an antisense oligonucleotide of phosphorodiamidate morpholino oligomer (PMO). Duchenne muscular dystrophy is a rare disease that primarily affects boys. It is caused by low levels of a muscle protein called dystrophin. The lack of dystrophin causes progressive muscle weakness and premature death.
References
- ↑ McArdle, Anne. (1993). Mechanisms skeletal muscle damage in the dystrophin-deficient MDX mouse (PhD thesis). University of Liverpool. OCLC 53496566. EThOS uk.bl.ethos.385144.
- ↑ Bulfield, G.; Siller, W. G.; Wight, P. A.; Moore, K. J. (1984). "X chromosome-linked muscular dystrophy (mdx) in the mouse". Proceedings of the National Academy of Sciences of the United States of America. 81 (4): 1189–1192. Bibcode:1984PNAS...81.1189B. doi: 10.1073/pnas.81.4.1189 . PMC 344791 . PMID 6583703.
- ↑ "Animal Models - Parent Project Muscular Dystrophy". parentprojectmd.org. Retrieved 2016-05-03.
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