Large-Scale Production of High Purity Human Cortical Glutamatergic Neurons

Project Summary AbstractThere exists a dire need for new and more effective drugs to treat disorders of the central nervous systemCNSespecially in mental healthThe pace of approval for new chemical entities is anemicwith an average of just three compounds per year entering the market over the lastyearsUnsurprisinglyclinical trial failure rates for CNS drug development remain greater thanand many more programs fail during preclinical developmentGiven the immense personalsocietaland economic burden that psychiatric disorders place on the United Statesbetter drug discovery and development paradigms must be implementedBrainXell is addressing this issue by introducing new in vitro model systems with high relevance to the human brain that are composed of normal cultured human neurons of various typesThis proposal focuses on one of these typescortical glutamatergic neuronswhich is central to many psychiatric and neurological disordersIn our Phase I projectwe developed a novel and proprietary cocktail to expand cortical glutamatergic progenitorsallowing generation ofglutamatergic neurons from a single induced pluripotent stem celliPSCThis expansion method exhibits a clear advantage over traditional approaches that use growth factorssuch as fibroblast growth factorFGFand or epidermal growth factorEGFas glutamatergic progenitors expanded under such conditions often change their differentiation potentialWe have also optimized the cell dissociation process and neuron cryopreservation mediumwhich yield cell viability rtafter dissociating into single cells and rtafter thawingTogetherthese studies provide the technical basis to accomplish the same goalmanufacture large scalehigh purity cortical glutamatergic neuronsThis technology developed in Phase I will be fully commercialized in Phase IIWe will produce multiple large lots of normal neurons to validate our protocolOur procedures will be augmented with new equipment to ensure consistency between vials and lotsThe characterization and quality control procedures for the resulting product will be optimized and expanded to provide customers with a complete data set and clear quality criteria for the neuronsContinuing our focus on product performance for our customerswe will generatebest practiceprotocols for the end user that give guidance for culturing neurons in a range of systemsBecause glutamatergic neuron production will be offered as a servicewe will also test our methods on outside iPSC lines derived from individuals with schizophrenia and healthy controlsFinallywe will populate our product pipeline by developing protocols to produce glutamatergic neurons specific for superficiallayer II IIIcortical layers