Neurxtem Neural Organoid Human Platform Development for Substance and Opioid Use Disorders

This is a SBIR proposal from Neurxstem Inc., a company selected by NCET2 as a “Best University Startups 2016” is in response to the NIH HEAL initiative. Neurxstem’s goals are to develop and optimize a proprietary induced pluripotent stem cell derived human Neural Organoid Platform (NNOP) to develop 1) an early diagnostic NNOP for substance (SUD) and opioid (OUD) use disorder susceptibility and 2) to identify early therapeutic targets for future screens for effective SUD/OUD disease-related drug discovery, efficacy and safety screening. The current state of the art technology for such goals ranges from human primary and immortalized cell lines to rodent models. Because these models are poor surrogates for the complex network structure of the human brain, the proposed platform is expected to fill a crucial gap in translational neuroscience goals to understand and treat human brain disorders. Neurxstem has developed the proprietary methodology to make nearly complete human neural organoids and has shown that a superior NNOP compared to other ‘organoids’ that has all the major parts of the brain – retina, cortex, midbrain, hindbrain, and spinal cord - in a single, networked and scalable NNOP that also expresses all the major cell types including the microglia critically involved in SUD and exhibits responses to a drug of addiction that alters a multitude of biomarkers linked to multiple drugs of abuse. Neurxstem, a small business founded by Dr. Rene Anand, one of the technology inventors, proposes to further develop this clinically corroborated model system to test its reliability, reproducibility, robustness and utility for commercial translational neuroscience applications for SUD/OUD and initiate market entry after FDA approval. Phase I Aims: The Phase I goals are to identify early therapeutic targets by: 1) mathematical modeling of gene expression data responses to drugs of addiction to deduce early biomarkers for SUD/OUD. Phase II Aims: One goal is identify all possible early therapeutic targets by mathematical modeling from multiple data points and drug exposure samples for future SUD/OUD countermeasure development with Pharma. A second goal is to scale and validate the platform with multiple SUD patient iPSC lines to demonstrate: a) reliability, b) reproducibility and c) robustness metrics needed to demonstrate the full utility for early diagnostic and drug discovery, efficacy and safety testing commercial goals for SUD/OUD. Additionally, Neuxstem’s commercialization plan includes 1) market feedback from prospective clients for product validation; 2) initial market entry with beta customers/ business partners; and 3) continuing intellectual property development and prosecution. Fundamentally, the further development and validation of Neurxstem’s NNOP should provide a lower cost, more precise and accurate system for personalized, predictive diagnostic medicine and development of countermeasure for SUD/OUD.Narrative Current state of the art technologies for CNS disease mechanism studies and drug discovery include human cell lines to rodent models. These models poorly reflect the complex structure of the human brain and are failing in their predictive capacity in translational medicine applications. The proposed proprietary induced pluripotent stem cell-derived human neural organoid model system that yields clinically corroborated preliminary results for a drug of abuse is expected to fill this crucial gap for future translational neuroscience goals to understand and treat substance and opioid use disorders. 1