High-content screen to identify small molecule… (R41AG087802) – Project Grant to Mcm6 Therapeutics, Inc.

Abstract: Genome-wide association studies demonstrate that the top genes associated with increased risk for alzheimer's disease (ad) are involved in cholesterol and lipid metabolism, inferring lipid dysregulation is pathological. In particular, APOE4 is the strongest genetic risk for late-onset ad. Individuals of european ancestry carrying two copies of the APOE4 allele have a sixteen-fold increase in ad risk compared to a similar individual carrying two copies of the APOE3 allele. Apoe is the primary cholesterol and lipid transporter in the brain. Studies using induced pluripotent stem cells (ipsc) show that APOE4 alters cholesterol and lipid homeostasis across multiple cell types; however, its effects are especially pronounced in oligodendrocytes-myelinating cells that insulate and protect neurons. Histological and lipidomic profiling of human post-mortem brains and animal models shows impaired cholesterol transport and vast lipid deposits in APOE4-expressing oligodendrocytes. This aberrant accumulation of lipids impairs myelination, impedes amyloid plaque clearance, and increases neuroinflammation. Despite the central role of APOE4 and lipid metabolism in ad, no therapeutics target APOE4 or aberrant lipid accumulation. MCM6 therapeutics' chief science advisor, DR. Joel blanchard, an associate professor of neuroscience at the icahn school of medicine at MT. Sinai, has developed a drug discovery pipeline that models APOE4 lipid accumulation in human oligodendrocytes. In a small proof-of-concept screen, we discovered two mechanistically distinct drugs, rosiglitazone and cyclodextrin, both reduce lipid deposits in APOE4 oligodendrocytes. This reduction in intracellular lipid accumulation restored myelination in an in vitro neuron CO-culture assay and improved learning and memory in APOE4 transgenic mice. We will further optimize and apply this high-content screening pipeline to identify therapeutics that reduce aberrant cholesterol and lipid accumulation in human APOE4 oligodendrocytes. Aim 1, we will adapt our screening assay to 384-well plates, and perform a targeted screen of ~2,500 lipid modifying compounds. Our high-content image analysis platform will be conducted in collaboration with phenovista. We expect the focused screening approach in aim 1 will generate early leads and targets that we will validate and expand on with structure-activity-relationship studies. Aim 2 we will perform a large unbiased screen of 30,000 compounds. Hits from aims 1 and 2 will be validated via dose titration, and identity will be confirmed by RE-ordering and MS analysis. We will perform off-target analysis, functional validation (in vitro myelination), and neurotoxicity assays in ipsc-derived human brain tissue. Through rigorous in vitro validation of efficacy, selectivity, and neurotoxicity, we will select 3-10 lead compounds for future evaluation in our established APOE4 humanized mouse models through extensive histological and behavioral assays, delivering first-in-class lead compounds that restore APOE4 brain lipid homeostasis, opening new therapeutic opportunities in ad.

Action	Obligated	Date
Amendment	$0	Aug 15, 2025
Original award	$473,216	Sep 24, 2024

High-content screen to identify small molecule therapeutics that reduce aberrant lipid accumulation in APOE4 alzheimer's disease

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