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
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.
For more information about MS and ongoing research, see selected websites below.
http://www.msif.org/en/: The website of the Multiple Sclerosis International Federation gives independent information from MS professionals worldwide:
http://www.emsp.org/: 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.
Epilepsy is a common neurological disorder characterised by recurrent seizures due to the hyperexcitability and hypersyncrhonisation of neurons. Among the different epileptic syndromes, Mesial Temporal Lobe Epilepsy (MTLE) is the most common. Several recent studies using animal models have shown that a strong neuroinflammation occurs during MTLE leading to neurodegeneration of specific populations of neurons in the hippocampus as well as neuronal excitability and occurrence of spontaneous seizures.
Drugs currently available for the treatment of epilepsy targeting neuroinflammation process (steroids, plasmapheresis or intravenous immunoglobulin injection) have shown varying effects in randomized controlled clinical trial.
Role of NOX enzymes
In parallel, oxidative stress has emerged as a key factor that, similarly to neuroinflammation, not only occurs acutely as a result of status epilepticus, but contributes to epileptogenesis and chronic epilepsy. A pilot study recently performed by Neurinox partners showed a strong upregulation of NOX2 in the hippocampus of an animal model of MTLE-HS. The expression of NOX enzymes increased concomitantly with the establishment of chronic inflammatory phase. In addition, a substantial increase in NOX2 in the microglia was observed in the cortex of an epileptic patient. Today, efficient MTLE-HS treatment does not exist and NEURINOX will focus on this poorly explored aspect of epilepsy.
Work planned in Neurinox
Among the different animal models of MTLE, the unilateral intra-hippocampal injection of kainate (a glutamatergic excitotoxin) in mice has recently emerged. This injection into a specific brain region initially induces a focal status epilepticus. This is followed by a latent period of two weeks during which neurodegeneration and neuroinflammation are observed, as well as the progressive development of recurrent spontaneous hippocampal electrical discharges. The objective of Neurinox is to address the question whether inhibiting NOX enzymes (both genetically and pharmacologically) in rodent models is beneficial for the development of MTLE-HS.
Surgery to remove the brain area where epileptic seizures originate is a therapeutic option. Neurinox will have access to unique brain material from patients with MTLE-HS. This material will be compared with surrounding tissues to detect proteins, genes or molecules involved in NOX-mediated oxidation pathways.
www.epilepsy.com: A platform for information to patients, health professionals and researchers regarding epilepsy, treatments and ongoing research.
www.epilepsyfoundation.org: The website of the Epilepsy foundation gives information about the disease but also about different initiatives in research and possible funding and grant opportunities for researchers.