Bioartificial Brain Slices for Drug Screening

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): ISurTec is seeking NIH funding to develop a human bioartificial brain slice prototype, designed for use in electrophysiological drug-screening assays. Acute brain slices, prepared from rats or mice, are currently the 'gold standard' preparation for characterizing neural tissue responses to drugs, toxins, or other agents. However, the limited number of brain slices produced per animal, coupled with the high costs of animal care and use, remains a major limitation of this approach. Furthermore, due to interspecies genetic variation, preclinical data acquired through the use of acute brain slices wil usually be of limited predictive power for human clinical trials and postmarket surveillance. In this study, 3-dimensional neural circuit scaffolds will be patterned after the Schaffer collateral-CA1 pyramidal cell synapse of the hippocampus. 350 micron thick scaffolds will be prepared by laminating and annealing random nonwoven and aligned photoreactive nanofiber mats, following their photopatterned surface modification. The resulting bioartificial brain slice scaffolds will establish open field circuit architecture for co- cultured neuronal populations to generate postsynaptic field potentials in response to orthodromic stimulation. In Phase I, prototype scaffolds will be prepared and populated with E18 rat hippocampal neurons, to confirm the scaffold's ability to support the generation of robust postsynaptic field potentials. I Phase II, scaffolds will be populated with human neurons derived from expandable Neural Progenitor (hNP) cell lines. Terminal differentiation of hNPs in situ on growth factor-patterned scaffolds will also be investigated in Phase II. The bioartificial brain slice scaffold will be produced in a standardized format that is compatible with common electrophysiological equipment. Ultimately, we envision the scaffolds will enable electrophysiological assays with high predictive power for multiple neurotransmitter systems including glutamatergic, cholinergic, dopaminergic, and gabaergic synapses. Thus, the human bioartificial brain slice will be a valuable tool for drug development concerning a wide variety of human neurological diseases and disorders, including addiction, ADD/ADHD, depression, Parkinson's disease, pain processing, and schizophrenia. This technology will advance the field of HTS by overcoming two limitations of acute slices derived from rodents (1) limited human relevance and (2) high burden and cost of animal care compliance and oversight.