Amyotrophic Lateral Sclerosis (ALS)
Amyotrophic lateral sclerosis (ALS) is a relentless degenerative disease of the spine, and often of the brainstem, in which motor neurons gradually die, causing paralysis and death. The first symptom of the disease is muscle weakness in one or more limbs spreading progressively to all limbs and muscle groups, including the diaphragm, which results in respiratory failure. About 50% of patients die within 18 months of diagnosis. Despite the testing of a number of drugs, no treatment has ever extended life expectancy a few months beyond historical controls.
One of the most important discoveries in ALS research has been the identification of genetic mutations that cause familial ALS. Approximately, 10% of ALS is caused by mutations in an enzyme called superoxide dismutase 1 (SOD-1). A common feature of all ALS, both sporadic and familial, is the presence of large aggregates of SOD-1 in motor neuron cell bodies. This observation, together with genetic data, supports the idea that SOD-1 plays a central role in ALS pathology. Indeed, the generation of transgenic mice and rats that over-express human SOD-1 with point mutations (mSOD) that correspond to those found in humans resulted in animals that express all of the hallmarks of the human disease.
The motor neurons that die in ALS use glutamate to mediate neurotransmission and, as one might expect, surrounding astrocytes efficiently remove excess glutamate from synapses. In ALS patients, significant loss of EAAT2 expression has been documented. We have been exploring the use of RP-115 to follow this loss in a transgenic rat model of ALS and found that RP-115 does indeed describe the loss of EAAT2 in the spinal cord in line with disease progression. In a more recent study, we found the same loss of RP-115 in dogs that present a canine version of ALS. These dogs have been shown to carry mutations in SOD-1 just like the human familial ALS patients.
|These non-clinical data give us considerable confidence that RP-115 is likely to serve as a sensitive and effective diagnostic of ALS in humans and should be of use in tracking the efficacy of new therapies targeting this currently incurable disease. |