A MINIATURIZED AD MPS PLATFORM FOR HIGH-THROUGHPUT DRUG SCREENING

"Alzheimer Disease (AD) and Alzheimer Disease Related Dementia (ADRD) may include the neuropathological hallmarks amyloid, tau, neuroinflammation, synaptic and neuronal loss, and additional pathologies including TDP-43 in the case of the ADRD- Limbic predominant Age-related TDP-43 Encephalopathy (LATE). The first objective is to develop an isogenic APOE4 microphysiological system (MPS) with human induced pluripotent stem cell (iPSC)-derived neurons, astrocytes, and microglia assembled into a brain organoid or "assembloid", and establish two robust AD phenotypes that mimic the AD/ADRD microenvironment that can be used for drug screening. The second objective is to establish a proof-of-concept microfluidic high-throughput drug screening platform for MPSs using the established phenotypes of progranulin knockout MPSs to validate the delivery of therapeutics in formats amenable to high-throughput drug screening. This proposal brings together a multi-disciplinary team with expertise in generating iPSC-derived cells (NeuCyte), MPS development (UCSF) and microfluidics (Acoustic Bio) to accomplish these objectives. Successful completion of Phase I will translate to Phase II and validating highthroughput drug screening of the APOE4 MPS and potential commercialization of the platform."