Patients with mitochondrial myopathies, sometimes referred to as mitochondrial disease with myopathy, present a complex array of symptoms that can vary widely in terms of their severity, although the main symptoms that generally result from mitochondrial dysfunction include muscle weakness, exercise intolerance, and fatigue. Decreased muscle function can affect major muscle groups used for walking, climbing, lifting, and maintaining posture, and muscle weakness is also evident in smaller muscle groups that control, for example, movements of the eyes and eyelids. In addition to the skeletal muscular effects associated with mitochondrial dysfunction generally, patients with MM can also experience seizures, impaired gastrointestinal motility, impaired respiratory function, difficulty swallowing, impaired vision or hearing, and impaired balance and coordination. The prognosis for patients with MM varies widely depending on the degree of involvement of various organ systems in the disease, with disease progression leading to significant physical impairment and even to death in some individuals1,2.
There are currently no approved therapies for the treatment of MM. It is normally recommended that patients maintain a diet that is high in certain types of fat, low in sugar, and low in iron, take vitamins and supplements, and exercise regularly1. Resistance training has been shown to increase functional muscle tissue; however, exercise is not known to reverse the effects of the disease, and cessation of resistance training results in loss of muscle strength3. Patients with severe manifestations of certain MM may undergo surgery to address seizures, deafness, and cardiomyopathy4. Because omaveloxolone targets molecular pathways involved in impaired bioenergetics and chronic inflammation and penetrates the blood-brain barrier, we believe that the drug could provide a benefit to MM patients.
The prevalence of MM is estimated to range from 1 to 6 per 100,000 globally. There are fewer than 100,000 people globally with MM, including an estimated 20,000 to 40,000 in the United States5.
Mitochondrial myopathies, sometimes referred to as mitochondrial diseases with myopathy, are a multi-systemic group of myopathies associated with mitochondrial dysfunction that are caused by over 200 different genetic mutations. Despite the different array of symptoms of the diseases, a unifying feature of MM is dysfunctional mitochondrial respiration, which subsequently leads to a reduced ability to produce ATP.
Pathogenesis of mitochondrial myopathies comes from genetic mutation in the mtDNA or nuclear DNA that encodes for respiratory chain proteins. While the origination of the myopathies may vary, the histological effect of “ragged red fibers” is present in almost all patients6. This is due to non-uniform presence of cytochrome c oxidase (COX), an enzyme important in the electron transport chain that is encoded by both the nuclear and mtDNA genes. Its deficiency is suggestive of a mitochondrial myopathy6,7. The deficiency of COX in muscle fibers results in irregular cellular respiration and ATP production. Over time, this will result in deficient fibers and eventually lead to overall muscle atrophy. Many affected cells contain a mixture of healthy and defective mitochondria.
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- Goldstein and Wolfe. The elusive magic pill: finding effective therapies for mitochondrial disorders. Neurotherapeutics 2013; 10:320-8.
- MacFarland et al. The neurology of mitochondrial DNA disease. Lancet Neurol. 2002 Oct;1(6):343-51.
- Taivassalo and Haller. Implications of exercise training in mtDNA defects–use it or lose it? Biochim Biophys Acta. 2004 Dec 6;1659(2-3):221-31.
- Parikh et al. A modern approach to the treatment of mitochondrial disease. Curr Treat Options Neurol. 2009 Nov;11(6):414-30.
- Schaefer et al. The epidemiology of mitochondrial disorders—past, present and future. Biochim Biophys Acta. 2004 Dec 6;1659(2-3):115-20.
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- Murphy et al. Cytochrome c oxidase-intermediate fibres: Importance in understanding the pathogenesis and treatment of mitochondrial myopathy. Neuromusc Disord. 2012; 22:690-98.
- Neymotin et al. Neuroprotective effect of Nrf2/ARE activators, CDDO ethylamide and CDDO trifluoroethylamaide, in a mouse model of amyotrophic lateral sclerosis. Free Rad Biol Med. 2011; 51:88-96.
- Saha P et al. The triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic-acid methyl ester has potent anti-diabetic effects in deit-induced diabetic mice and Lepr(db/db) mice. J Biol Chem. 2010; 285:40581-92.