Unmet Need
The WHO has predicted that neurological disorders (NDs) will become the second leading cause of death in 20 years after cardiovascular diseases. Various proteins have been identified to aggregate and accumulate in the brain depending on the indication: amyloid-beta or tau in Alzheimer’s Disease, alpha-synuclein in Parkinson’s disease, and TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis. Despite all the knowledge accumulated on topic, NDs remain incurable and have quickly become one of the largest public health problems. There is a consensus that the key event common to NDs is the misfolding, oligomerization, and accumulation of protein in the brain. Phenotype screening has emerged as a powerful technique because they may represent a more holistic model of disease states as opposed to biochemical screens, however there has not been a reproducible technique that mimics protein aggregation. These phenotype screens are paramount for therapeutic purposes, and there is an increasing need to find novel drugs which can abate or slow down the course of NDs.
Technology Overview
Johns Hopkins researchers have developed optogenetics-assisted method of alpha-synuclein aggregation induction system (OASIS). This technology presents a model for Parkinson’s disease (PD) for candidate drug screening; as the field has struggled to attain a model of PD that reproducibly exhibits α-synuclein oligomerization and aggregation. The inventors successfully evaluated OASIS in midbrain dopaminergic neurons, derived from human induced pluripotent stem cells, to effectively mimic the phenotype of PD. The invention provides a platform to screen candidate drug molecules in a high-throughput fashion for PD.
Stage of Development
One of the applications of OASIS is to perform a phenotypic screening in human neurons, to identify potential drug candidates that can reduce/delay the pathogenic forms of alpha-synuclein aggregates. The inventors have optimized the protocol and has finished a small-scale pilot screening (~1,200 small molecules), which led to the identification of two promising candidates that can decrease the levels of pathogenic alpha synuclein aggregates, and also rescue the human dopaminergic neuronal cell death. Currently, the inventors are in the process of performing a larger-scale compound screen, with ~10,000 small molecules.
Publications
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