Multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), is the most common, non-traumatic disabling disease affecting those in early adulthood. Within 15 years after onset of the disease, fifty percent of patients need help walking. Worldwide, an estimated 2.5 million people are affected by MS, with increasing incidence and prevalence in both developed and developing countries.
The course of MS is extremely varied and unpredictable. MS is conventionally seen as a two-stage disease with early inflammation responsible for relapsing-remitting disease, the most prevalent form of the disease, characterized by episodes of neurological deficits. This is often followed by a non-relapsing progressive neurological deterioration over time. Symptoms include fatigue, cognitive impairment, spasticity, limb weakness, sensory loss, visual alterations and bladder dysfunction.
As there are currently no FDA-approved
curative therapies for MS, the objective of therapies for patients with MS are generally aimed at shortening the duration of acute exacerbations, decreasing their frequency, and providing symptomatic relief. Though there are FDA-approved therapeutic agents that can reduce disease activity and progression in some MS patients, not all patients respond well to treatment with these drugs, most likely due to the variability of the disease.
Oxidative stress and the related by-products, reactive oxygen or nitrogen species (ROS or RNS), have been associated with the development of many types of human diseases including neurodegenerative diseases such as MS Studies have increasingly demonstrated that ROS contribute to a number of mechanisms underlying the development of MS. ROS are produced with the interaction of monocytes, a type of white blood cell, with brain endothelium, the cells lining the brain blood vessels. This makes the brain blood vessels leaky, allowing white blood cells to get into the CNS. The white blood cells subsequently produce large amounts of ROS leading to ingestion of myelin and breakdown by macrophages, along with other nerve damage underlying the development of MS. A number of studies have also demonstrated that DNA damage and other oxidative stress biomarkers are increased in the peripheral blood samples of MS patients. The beneficial effects of various antioxidants in MS have been described, reinforcing the key part ROS play in the development of MS.
The importance of DNA repair genes and DNA repair in MS is suggested by the observation of a significant increase in total DNA (nuclear DNA and mitochondrial DNA [mtDNA]) damage in active MS lesions as compared with normal-appearing white matter (myelin coated nerve fibers) of MS brains. Investigations have further indicated that mtDNA is the form of DNA predominantly damaged. Gene expression studies have shown that multiple genes involved in DNA repair are differentially expressed in MS lymphocytes and lesions when compared to control genes including those, such as OGG1, that are involved in BER. The Ser326Cys gene polymorphism of OGG1 has been found to be a major genetic factor for individual susceptibility to develop MS. Treatment targeted to increase mtDNA repair function, therefore, could be a useful therapy for MS patients.