ALS HAS PROVEN difficult to treat because the underlying causes of selective motor neuron death are poorly understood, even in that population of patients in which the genetic mutations leading to the disease have been identified. Recent evidence indicates that a common factor underlying several chronic neurodegenerative disorders, including ALS, may be the initiation of a neurotoxic cascade resulting from the responses of neuronal mitochondria to oxidative stress (Lin and Beal, Nature 443:787-795, 2006). KNS-760704, our lead molecule, has been shown to have specific and significant effects the pr on neuronal mitochondria, including the modulation of aberrant mitochondrial large-conductance ion conductance pathways induced by stressors such as high calcium concentration and ubiquitin proteasome inhibition.
The Knopp Neurosciences discovery program is focused on the role of mitochondrial dysfunction in selective motor neuron death and further elucidating the mechanisms by which KNS-760704 and related molecules provide protection from oxidative stress and other initiators of neuronal death. An additional goal is the identification of biomarkers of disease progression and drug effect in motor neuron degeneration.
To accomplish these goals, Knopp Neurosciences has initiated research projects to understand the biochemical pathways involved in drug action in the mitochondria, including the role of proton leak in the determination of the efficiency of oxidative phosphorylation, and its role in determining relative risk of death in neurons. Knopp’s scientific leaders bring decades of expertise in molecular biology and neurophysiology to these investigations. These projects have been initiated in both our Pittsburgh laboratories and via collaborations with leading research institutions in the U.S. and Europe.