CSO: Dr. Rachel Eren
Nevrox, is a drug discovery company developing a neuroprotective small molecule modulator of protein disulfide isomerase (PDI) for the treatment of Huntington disease (HD) and Amyotrophic Lateral Sclerosis (ALS).
PDI, is a thiol-oxireductase protein located in the endoplasmic reticulum (ER), serves two major functions: (1) general chaperone activity; (2) oxidation, reduction and isomerization of protein disulphide bonds. A by-product of the latter function is generation of reactive oxygen species (ROS), specifically H2O2. While ROSs have various physiological roles, their accumulation, known as oxidative stress, is toxic to cells. In healthy cells, accumulation of ROSs is prevented by the cell’s natural antioxidant mechanisms, but in neurodegenerative diseases, oxidative stress is considered a major factor in ongoing cell damage. In light of the physiological roles of ROSs, general ROS targeting has shown disappointing therapeutic effect. Inhibition of PDI’s redox activity may provide specific, disease relevant, ROS targeting.
Neurodegenerative disorders constitute a class of diseases that express characteristic misfolded proteins that aggregate and induce neuronal toxicity and death.
Huntington disease (HD) is one such fatal protein misfolding disease that afflicts primarily medium spiny neurons in the striatum. HD is caused by expansion to more than 36 CAG trinucleotide repeats in the huntingtin gene (Htt). Although the mechanisms through which mutant Htt (mHtt) is deleterious to neuronal function remain elusive, accumulating data from HD models as well as from human post-mortem brain analyses suggest that endoplasmic reticulum (ER) stress and oxidative damage are important contributors to mHtt toxicity in neurons. HD is a rare disease that affects 5 to 10 per 100,000 people in the European and USA. Currently, there is no cure for HD and available treatments can only assist patients with management of selected symptoms.
ALS is characterized by the degeneration of upper motor neurons of the motor cortex and lower motor neurons of the brainstem and spinal cord. This degeneration results in symptoms of fatigue, muscle weakness and atrophy, followed by eventual paralysis. ALS is an orphan disease (estimated 50,000-70,000). Effects usually age ≥40 years, with peak incidence at 65-74 years. Median survival is only 3-4 years from onset. 15% of patients live over 5 years, and only 5% over 10 years. Sporadic ALS accounts for 90-95% of cases, and hereditary ALS for the remaining 5-10%. There are only two approved drugs: Riluzole and Radicava with most patients receive Riluzole.
Professor Brent R. Stockwell, PhD, Inventor and advisor
Dr. Stockwell is a Professor at Columbia University with joint appointments in the Department of Biological Sciences and the Department of Chemistry; he is also a member of the Motor Neuron Center and the Cancer Center at Columbia University Medical Center. Dr. Stockwell is the author of >100 scientific publications, 43 published patent applications and 18 issued US patent.