Large-Scale Production of High Purity Human Neurons for CNS Drug Discovery

DESCRIPTION provided by applicant The personal societal and economic burden that disorders of the central nervous system CNS place on the United States is tremendous For mental health care alone direct costs were estimated at $ billion annually This is in part due to failures in developing effective medications From the FDA approved just new drugs to treat CNS disorders covering the clinical areas of neurology psychiatry and pain That averages to just three new chemical entities NEIs per year while clinical trial failure rats for CNS drug development remain greater than Although the reasons for this exceedingly high level of attrition are myriad and complex the central challenge to drug development is that platforms for early preclinical identification and validation of novel compounds are often not relevant to the target disease BrainXell Inc seeks to address these issues head on by generating in vitro model systems that more closely approximate the human CNS This SBIR Phase I proposal is to produce large quantities of highly enriched functionally specialized neurons of consistent quality that meet high throughput screening HTS requirements We have selected cortical glutamatergic neurons as the neuron subtype for this project These neurons are affected in a large number of psychiatric diseases including depression and schizophrenia We have engineered a human iPSC line with constitutive expression of nanoluciferase allowing us to evaluate combinations of small molecules designed to rapidly expand cortical neural progenitors This goal will be achieved by modifying approaches used previously to generate large numbers of highly pure motor neurons We will also identify and develop novel dissociation solutions and freezing media to promote survival following disaggregation and thawing thus reducing costs and making it practical for HTS Formulation of an effective cocktail for expanding and maintaining cortical progenitors will not only enable us to manufacture cortical glutamatergic neurons for HTS from normal as well as patient iPSCs but also provide the technical basis to accomplish the same goal with other neuronal subtypes such as cortical GABAergic neurons or midbrain dopaminergic neurons PUBLIC HEALTH RELEVANCE BrainXell will develop technology to produce large quantities of a specialized human nerve cell in a consistent manner Such cells could be used to discover new drugs for the treatment of psychiatric diseases such as depression anxiety and schizophrenia