Alzheimer Disease (AD) is characterized by b-amyloid (Ab) accumulation, neurofibrillary tangles (NFTs),neuroinflammation, and widespread neuronal and synaptic loss. To date, there are no therapies available,although immunotherapies i.e., Lecanemab hold promise. Species differences underlie the difficulties intranslating therapeutics uncovered in animal models for human brain-specific diseases, e.g., AD and AD-relateddementia (ADRD). Human induced pluripotent stem cell (hiPSC) technological advances enable better human-specific disease modeling, particularly when disease-related genetic mutations are absent in murine or rodentmodels (e.g., many AD GWAS genes), but face challenges due to the difficulty in mimicking the in vivo contextin current in vitro models. Microphysiological systems (MPS) with defined cellular compositions can providescalable, reproducible brain models that better recapitulate the in vivo environment, in which preclinical drugdiscovery efforts can translate to a higher success rate for identified targets and compounds. This projectproposes the development of a mini-brain assembled organoids (assembloids) microfluidics platform using ADpatient-derived APOE4 and isogenic gene-edited APOE3 iPSCs to facilitate effective and reproducible screeningfor AD therapeutics. NeuCyte employs robust differentiation protocols to generate neurons, astrocytes, andmicroglia in large quantities facilitating the generation of NeuroImmune Assembloids (NIA) in which the 3Dmicroenvironment recapitulates salient ex vivo brain phenotypes, e.g., neurodegenerative and cell-type specificphenotypes due to a genetic mutation, enabling improved translatable high-throughput preclinical drug discovery.While isogenic, this platform is also modular, i.e., the impact of a mutation in microglia can be studied to modeleffects on neurons facilitating mechanistic studies mimicking the cellular complexity of the human brain. TheAD/ADRD MPS microfluidic platform incorporates acoustic technology and enables economical examination ofAD pathology in vitro facilitated by miniaturization, reducing costs associated with cell numbers, reagents, anddrug library quantities to facilitate high-throughput drug screening. Successful completion of Phase I will establishthe feasibility for commercialization of an AD/ADRD drug screening platform.
Public Health Relevance Statement: Narrative
Alzheimer Disease is the most common age-related neurodegenerative disorder. Sporadic late-onset AD
represents the majority of cases. The exponentially aging patient population means the healthcare burden will
also increase exponentially. In this collaborative proposal, NeuCyte is partnering with UCSF and Acoustic Bio to
establish a reproducible, cost-effective microfluidics-based screening platform using mini-brain assembled
organoids (assembloids) for sporadic late-onset Alzheimer Disease. These assembloids are more representative
of the human brain because they can be coaxed into developing Alzheimer, which will allow pharma to test their
compounds to identify new AD therapies to address this growing healthcare crisis.
Project Terms: <µfluidic><Ï mutation> | | | 