Molecular Glue Degraders Targeting APP for Prevention and Treatment of Down Syndrome-Associated Dementia

About This Grant

Project Summary/Abstract Down syndrome (DS), caused by trisomy of chromosome 21, affects approximately 1 in 700 live births worldwide. Despite advances in prenatal diagnosis and maternal screening, the incidence of DS has not declined, and its prevalence continues to rise due to increased maternal age and longer life expectancy. Nearly all individuals with DS develop Alzheimer’s disease (AD)–like pathology and dementia (DSAD) by middle age, primarily due to triplication of the amyloid precursor protein (APP) gene on chromosome 21. Overexpression of APP leads to elevated amyloid-β (Aβ) production, aggregation into plaques, and progressive neurodegeneration and dementia. Recently, Aβ-targeted monoclonal antibodies such as donanemab have been approved by the FDA for early-stage AD, and clinical trials are underway to evaluate their efficacy in DS. However, antibody therapies face major challenges in crossing the blood–brain barrier (BBB) and are associated with serious adverse effects, including cerebral hemorrhage. Thus, there remains a critical unmet need for effective strategies that directly and selectively target APP in DS. To address this need, we have developed a targeted protein degradation (TPD) approach and discovered molecular glue degraders that selectively promote lysosomal degradation of APP and reduce Aβ production in induced pluripotent stem cell (iPSC)–derived neurons from AD patients. These degraders bind at the interface between APP and CAPRIN1 (cytoplasmic activation/proliferation–associated protein 1), stabilizing their interaction and triggering CAPRIN1-mediated lysosomal degradation of APP. Our lead compound crosses the BBB, is orally bioavailable, and significantly reduces APP levels and Aβ plaque burden in AD mouse models. Using AI-assisted ligand- and structure-based drug design, we have generated a focused library of optimized lead derivatives. Building on this breakthrough, the objective of this exploratory project is to evaluate the therapeutic potential of APP molecular glue degraders for treating DS. In Aim 1, we will screen our AI-designed compound library in DS patient–derived iPSC neurons to identify candidate compounds that selectively degrade APP via the CAPRIN1-dependent lysosomal pathway. Promising compounds will be further characterized for ADME (absorption, distribution, metabolism, and excretion) properties to identify potent, metabolically stable candidates for in vivo testing. In Aim 2, the top optimized compounds will be evaluated for pharmacokinetics (PK), BBB permeability, off-target activity, and toxicity using standard repeated-dose studies in euploid mice. One optimized compound will then be tested for therapeutic efficacy in the Ts65Dn DS mouse model to determine if oral administration reduces APP, Aβ40, phosphorylated tau, and neuroinflammation, and preserves or improves cognitive function. Successful completion of this project will provide proof of concept for APP-targeted molecular glue degraders as first-in-class therapeutics to prevent the progression of DS to DSAD and will establish a powerful TPD and AI-integrated framework for drug discovery in DS.