A Humanized Organ Plate Paradigm for High Throughput Alzheimer's disease Therapeutics Abstract Preclinical drug discovery research for Alzheimer's Disease (AD) is hampered by the lack of sufficient preclinical models. Although several drugs have shown promise in animal models to some extent, many human clinical trials of therapies for AD have failed. Therefore in vitro models using human-derived cell lines or patient-derived genetically-manipulated human induced pluripotent stem cells (hiPSC) that overexpress the different isoforms of β-amyloid have shown interest. These hiPSCs with the acquisition of full cellular functionality, microenvironment mechanostructural cues and mimicking vascular defects observed in patients with AD are in development. Further, blood-brain-barrier (BBB) integrity that prevents neurotoxins from entering the brain and bidirectional molecular communications between the central nervous system and the enteric nervous system, are critical for AD therapeutic strategy in the laboratory models. These models with 3D perfused engineered micro-sized organ systems can help costly and risky drug testing with quantitative and mechanistic data. However, high throughput portable passive system that can connect multiple organs and provide quantitative pharmacokinetics data, is still to be realized. Therefore, Biopico Systems Inc teams with UC Irvine to propose a Humanized Organ Plate Paradigm (HOPP) for high throughput Alzheimer's disease therapeutics that can accurately and reproducibly mimic the AD phenotype in vivo and be amenable to high-content screening and assay applications. With the preliminary results from the patent-pending organ platform and measurement instrumentation, Biopico will utilize existing drugs that have failed in clinical trials and given positive indications to perform proof-of-concept of our platform. The Phase I research aims are to: (i) Develop functional blood-brain-barrier in vitro pharmacological HOPP system in high throughput format, (ii) Integrate multi-organs for morphological, functional, gene expression & metabolic markers metrics and (iii) Validate HOPP system using pharmacokinetic modeling and in vitro to in vivo extrapolation. The successful completion of these aims will provide a strong foundation for developing a commercial organ system in Phase II to customers developing therapeutic agents for AD. Biopico's vision is to commercialize the largescale application of the screening assay to accelerate the process of finding a disease-modifying therapy.

Narrative We will develop the multi-organ high throughput PK/PD screening in humanized in vitro drug testing for AD. The development of this high throughput body-on-a-chip platform with patient-specific stem cells and immune cells is a powerful new approach to advance AD therapeutics. Thus the gut-liver-kidney-brain platform will enable the development of in vitro clinical trials for drug discovery and drug efficacy and validate therapeutic targets.