Rapid drug repurposing for rare disorders by pooled image-based profiling - PROJECT SUMMARY Collectively, rare diseases are common, affecting nearly 1 in 10 in the U.S.A. Unfortunately, ~90% lack approved treatments. Traditional drug development is prohibitively slow and costly, especially for rare disorders with small patient populations and lacking screenable phenotypes. Recently, we discovered that 16% of pathogenic genetic coding variants cause protein mislocalization. This makes microscopy-based drug screens possible for the hundreds of diseases we uncovered, but with current technology millions of tests would be required to test even just FDA-approved drugs - too expensive for non-profits and not profitable for companies. We propose to develop and test RAPID (Rare disease Analysis through Pooled Image-based Identification of Drugs), a novel, massively parallel platform to overcome this bottleneck. RAPID integrates pooled optical variant identification, high-dimensional image-based profiling, and advanced computation, enabling simultaneous testing of an approved drug against hundreds of barcoded disease phenotypes in a single microplate well, dramatically reducing costs. This offers a bold new approach to therapeutic discovery. We will test and validate 26,400 drug/disease combinations to identify candidate therapies in parallel. To accomplish this, we will: (1) develop the RAPID platform to conduct a pooled repurposing screen to identify therapeutic repurposing opportunities for 220 FDA-approved drugs across a set of 120 diverse diseases (for which we previously identified protein mislocalization phenotypes). (2) For the most promising drug-disease matches identified, we will carry out initial confirmation through dose-response analysis and connect with disease-specific experts and foundations to plan next steps, including validation in disease-relevant cell types where possible. All resulting data and code will be publicly available through established repositories (PubChem, Cell Painting Gallery, Github) and a user-friendly web portal, empowering the research community. RAPID would demonstrate a novel paradigm for parallelized drug discovery. Discovering a single useful treatment for a rare disease would be a victory for a $275,000-budget, exploratory R21; the project has the potential to uncover more. Furthermore, by establishing the success rate for this kind of screening, it would provide the rationale to scale up to thousands of drugs and many hundreds of diseases, and to expand to more physiologically relevant cell types such as neurons or cardiomyocytes. The project therefore provides potential near-term benefit for patients currently without therapeutic options as well as a blueprint for scalably screening additional drug libraries and disease variants in the future. RAPID moves beyond the inefficient one-by-one approach to accelerate parallel therapeutic discovery for rare diseases. Not all rare diseases will be treatable by correcting protein mislocalization, but novel technologies offer a unique opportunity to tackle a set of recently discovered diseases and deliver therapeutic hypotheses to clinicians, researchers, and patients.
