Human iPSC neural spheroids to screen for compounds that block tau propagation

RESEARCH & RELATED Other Project Information Novoron Bioscience, Inc. 7. PROJECT SUMMARY Approximately 6.9 million people aged 65 and older in the United States have Alzheimer’s dementia (AD).1,2 AD and other dementias are a major economic burden expected to cost $360 B in 2024, of which $231 B will be funded through Medicare and Medicaid.3 There is an urgent need to identify and develop disease-modifying therapeutics as current therapies only add 0.65 quality-adjusted life years and cost $130,000 per year.4,5 Tauopathies, including AD, exhibit prion-like neuron-to-neuron transsynaptic propagation of tau.6 Here, we propose a platform-based strategy to evaluate novel therapies designed to inhibit the propagation and aggregation of pathological tau. As part of this platform, we will use LRP1 (an established model known to influence tau propagation) WT and KO human induced pluripotent stem cell (hiPSCs) derived neural organoids to confirm that our system accurately detects changes in tau propagation. This robust, multi-faceted platform will enable the identification and validation of candidates that disrupt tau pathology, providing a path toward new treatments for AD and other tauopathies. Our team and others have shown that organoids generated from hiPSCs serve as a scaled-down and three- dimensional model of the human brain, mimicking various developmental features at the cellular and molecular levels. Unlike animal models, which do not always translate to human utility, or other in vitro models, which cannot capture the complexity of human tissues, organoids recapitulate aspects of in vivo brain development and function in a dish. Organoids are recognized for their usefulness as a translationally valid organ-level platform in the drug discovery space for colon cancer, cystic fibrosis, and precision therapy. Cortical organoids have further proven to be informative models of human brain development, tissue organization and cell-cell interactions, and maturation, suggesting a likely utility in therapeutic advancement. Cortical organoids retain properties of a neural organ to a large degree, including integration of supporting cells, cytoskeletal structuring, cellular organization into particular regions, and in some cases, in vivo-like spontaneous network activity. Our team recently used Rett syndrome organoids to identify donepezil (approved for AD as Aricept) that is now entering a DOD-funded Phase II clinical trial. We will create LRP1 WT and KO organoids to optimize and validate the utility of the organoids in screening with control compounds and the ability of the experimental small molecules to modulate tau propagation. This project brings together the expertise of Novoron Bioscience, BrainStorm Therapeutics, and Defined Bioscience to develop human-relevant brain models for drug discovery. By employing advanced hiPSC-derived cortical brain organoid technologies, we aim to establish a scalable, high-throughput screening platform to identify small molecules that disrupt tau-LRP1 interactions. The project addresses critical unmet needs in Alzheimer’s drug development and will generate new insights into tau pathology mechanisms.