Background information
Multiple sclerosis (MS) is one of the most common diseases of the central nervous system (CNS). It is an inflammatory disease leading to myelin damage which results in the disruption of transmission of neural impulses that causes progressive physical and cognitive disabilities.
The cause of MS is not known. Multiple features of MS pathobiology suggest that myelin damage is caused by autoimmune response (an abnormal reaction of immune system against components of myelin leading to its destruction). The range of symptoms is very wide and depends on the particular regions of the CNS affected by the lesion.
Most common symptoms include visual problems, balance and coordination problems, spasticity, altered sensation, pain, fatigue, cognitive and emotional disturbances, bladder dysfunction, sexual dysfunction, etc MS prevalence ranges between 2 and 150 per 100,000, but MS is much more common in northern latitudes. Disease onset usually occurs in young adults and affects 3 times more females than males. MS takes several forms: about 85% of patients are diagnosed with relapsing-remitting form of MS characterized by attacks during which the new symptoms appear followed by total or partial recovery; about 15% of patients are affected by progressive form of MS with symptoms slowly accumulating over time.
There is no cure for MS. Available treatments attempt to enhance functional recovery after an attack, prevent new attacks, and ease the disabling symptoms. Administration of β-interferon 1a shows some beneficial effects in a subset of patients, but, despite claims to the contrary, their ability to modify disease course has not been clearly established.
Antibodies to α4-integrin (Natalizumab) suppress the extravasation of lymphocytes into the CNS, but gives a risk for tprogressive multifocal leukoencephalopathy. Inhibition of the sphingosine-1-phosphate receptor (Fingolimod®) results in the sequestration of lymphocytes in lymph nodes also resulting in therapeutic effects. Use of drugs which non-specifically suppress the immune system (glucocorticoids and the antineoplastic agent mitoxantrone) may slow the progression of the disease but are associated with harmful side effects.
Role of NOX enzymes in MS
Oxidative damage is a known feature of MS. Interestingly, on the contrary to many other neuroinflammatory conditions, ROS produced by NOX2 have been shown to be anti-inflammatory in autoimmune diseases. Indeed low ROS generation by NOX2 appears to prevent autoimmune responses in the chronic model of MS. NOX2-dependent ROS of antigen presenting cells are a key regulator of T cell activation. Interestingly, leukocyte ROS production correlates inversely with disease severity in MS and other autoimmune conditions such as Guillain Barré syndrome GBS.
Work planned in Neurinox
Based on the evidence given above Neurinox proposes NOX enzymes as potential pharmacological target for MS therapy. The expression of oxidative stress related genes will be analysed in different in vivo models of MS. Neurinox partners will develop small molecules NOX activators which will be validated in different animal models of MS. The effect of compounds on demyelination and neuronal death will be evaluated. Key findings from animal studies and oxidative stress analyses will be considered for validation in human clinical samples (serum, CSF) from patients with MS.
More information
For more information about MS and ongoing research, see selected websites below.
The website of the Multiple Sclerosis International Federation gives independent information from MS professionals worldwide:
EMSP is an umbrella organisation for 37 MS societies from 34 European countries. EMSP represents their interests at the European level and works to achieve its goals of high quality equitable treatment and support for people with MS throughout Europe.
The NEURINOX project has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement n°278611