Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motoneurons. Motoneurons control the function of muscle, therefore if they die, muscles are unable to function and they gradually weaken. Eventually, the ability of the brain to control muscle is lost, which leads to complete paralysis and ultimately to death from lung failure approximately 5 years after disease onset. ALS is a rare disease as its prevalence is around 2 per 100,000, but as of today, there are no treatments that can arrest, or even substantially delay, the progression of ALS. The only drug approved to treat ALS patients is Riluzole™, which is thought to inhibit the presynaptic release of glutamate. However its therapeutic benefit is extremely modest as in randomized controlled trials, it prolonged survival by approximately 4 months a beneficial effect which is subjectively not perceived by patients, family members or physicians.
Although the exact cause of ALS is unknown, many genetic mutations have been identified and specific features are invariably found, such as aggregation of specific proteins, such as TDP-43 and a strong inflammatory component. Numerous pharmacological targets has been described in animal models of ALS (anti-inflammatory drugs, anti-glutamate agents, neurotrophic factors, antioxidant, anti-apoptotic, gene inductors, autophagy inducers), but none of them significantly prolonged survival or improved quality of life when translated to ALS patients.
Role of NOX enzymes
Signs of oxidative stress are observed in ALS rodent models and in ALS patients. NOX2 and subunits are strongly upregulated in both ALS mice and patients. Recently, independent studies have shown impressive improvement in survival of ALS mice intercrossed with NOX1 and NOX2-deficient mice as well as delayed neurodegeneration. Because of absence of treatment and the inexorable development of ALS, there is a real need for testing new targets for pharmacological approach of ALS. In spite of important differences in the protective potential of NOX inhibition in ALS mice, these preliminary proof of principal experiments converge at identifying NOX enzymes as primary target for a potential treatment of ALS.
Clinical studies and trial planned in Neurinox
The underlying hypothesis of Neurinox is that NOX enzymes are a potential pharmacological target for ALS therapy. Small molecules NOX inhibitors are tested in an animal model of ALS (the SODG93A mouse). In case a molecule shows benefit in the animal model, it is planned to organise a clinical trial to test safety and efficacy of the drug.
Another important aspect Neurinox will focus on is the identification of laboratory readouts permitting to assess the progression of disease and to evaluate the efficacy of treatments (biomarkers). One of the potential biomarkers is NOX2 activity levels in blood. Therefore, levels of NOX2 activity in the blood of ALS patients will be compared to people not affected by the disease. Other molecules, oxidised biomarkers (isoprostanes and neuroprostanes) will also be measured as potential biomarkers of ALS.
A comprehensive description of current clinical trials and ALS research can be found on the excellent website of the ALS Therapy Development Institute: http://www.als.net
The NEURINOX project has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement n°278611