Drug Discovery at Neuropore Therapies
Our research and drug-discovery efforts are founded on a fundamental concept that the accumulation of specific misfolded, aggregated and thereby toxic neuronal proteins play a key role in the pathology of nearly all neuro-degenerative diseases.
Our development strategy includes two parts:
- Inhibiting the formation of specific membrane-embedded oligomeric protein aggregates
- Restoring the function of the cell’s natural mechanisms for removing these toxic protein aggregates.
Together with academic collaborators at the University of California San Diego, we have developed an in-depth understanding about how misfolded proteins embed and oligomerize in cell membranes leading to disruption of cellular function and ultimately cell death (1, 2, 3, 4). This understanding has enabled us to develop unique drug-candidates that specifically target this pathological process and preserve cellular function.
Our most advanced therapeutic candidate (NPT200-11), is being developed for the treatment of Parkinson’s disease and related “synucleinopathies”. Parkinson’s disease is a common debilitating neurodegenerative disorder affecting 1 in 100 persons over 60 that is characterized by the accumulation of large aggregates of the misfolded synaptic protein alpha synuclein. Numerous findings, including those from human genetic studies (5, 6, 7) and from studies by our academic collaborators with transgenic animal models (8, 9, 10), demonstrate the key role of misfolded alpha synuclein in the pathology of Parkinson’s disease. Our novel molecules prevent the formation of toxic oligomeric aggregates of alpha- synuclein in cell membranes and also the consequent toxic effects of these aggregates on cell function (11). NPT200-11 has been shown to improve motor function and other markers of neurodegeneration in a number of different animal models of Parkinson’s disease (12). With our partner UCB we are currently advancing NPT200-11 through Phase I clinical trials.Our lead compound (NPT200-11) for our alpha-synuclein program is currently in clinical development (phase 1) for Parkinson’s Disease.
In addition to our program targeting the oligomerization of alpha-synuclein for treating Parkinson’s disease we have a similar program aimed at developing compounds which prevent the formation of toxic aggregates of amyloid-beta protein. Misfolding and aggregation of this protein plays a key role in the pathology of Alzheimer’s disease. Our efforts to target amyloid beta have resulted in the discovery of a series of compounds that prevent the aggregation of amyloid-beta in cell based assays. Initial studies in animal models suggest that these (NPT400 series) compounds have beneficial actions on neuropathology in the appropriate transgenic animal models.
Targeting protein clearance mechanisms
Studies of human genetics indicate that impairment of protein clearance mechanisms is likely the most common cause of familial (genetic) forms of Parkinson’s disease and other neurodegenerative diseases (12, 13, 14). Studies in animal models further suggest that these impaired protein clearance mechanisms (called autophagy- Greek: 'self-eating' = self-clearance) may contribute to both genetic and non-genetic forms of the disorder (15, 16, 17, 18).
Neuropore Therapies has several programs that target specific mechanisms in autophagy, particularly, macroautophagy that is responsible for clearance of large misfolded protein aggregates as well as dysfunctional cellular organelles. (see 19-20 for reviews) As part of this effort we have developed a number of novel approaches to measuring the function of autophagy pathways in vitro and in animal models. We have also identified novel molecules that are now being evaluated as therapeutic candidates, and which could enter clinical development in 2016.