A massively parallel engine for drug discovery and repurposing in rare genetic diseases
The Challenge
Collectively, rare diseases are not rare. Approximately 10,000 distinct genetic disorders affect more than 300 million people worldwide, including 1 in 11 individuals in the United States. Despite rapid advances in identifying the genetic variants responsible for these conditions, traditional pharmaceutical pipelines lack the financial and logistical capacity to develop dedicated new treatments for thousands of individual diseases.
Drug repurposing (finding new therapeutic uses for existing, safe, FDA-approved compounds) offers the fastest path to clinical treatments. However, testing thousands of existing drugs against hundreds of rare disease models using traditional single-experiment methods would require millions of tests, creating an overwhelming experimental bottleneck.
Our Approach: Project Encore
To break through this bottleneck, the Neal lab at the Broad Institute is teaming up with the Carpenter-Shen lab at Purdue to build Encore, a massively parallel screening platform that merges pooled genetic screening with high-dimensional optical imaging and computer vision. Encore combines:
Cellular Profiling: A common mechanism of many rare genetic diseases is protein mislocalization, where a mutated protein fails to reach its proper location in the cell. Using multi-color fluorescence stains and signal amplification, Encore captures high-dimensional structural details across whole cells, enabling machine learning algorithms to distinguish disease-associated cell states from healthy ones.
Optical Barcoding: By labeling each genetic mutation with a unique optical barcode, Encore allows cells carrying hundreds of different rare disease variants to be pooled together in a single experiment. Optical sequencing reads these barcodes directly inside the cell after imaging, mapping each cell’s single-cell profile to its specific genetic variant.
Parallel Drug Screening: Instead of testing one disease and one drug at a time, Encore exposes hundreds of pooled disease variants to individual compounds, evaluating how effectively a drug reverts diseased cells back to a healthy profile across hundreds of conditions simultaneously.
Scope and Impact
Supported by an $8.8M NIH Director's Transformative Research Award, Project Encore will experimentally evaluate over 6,700 compounds from the Drug Repurposing Hub against hundreds of rare disease variants, testing more than 1.6 million drug-disease combinations. In parallel, our team will utilize image-based profiles to perform virtual compound screens across ~29 million additional drug-variant pairs.
By systematically uncovering candidate therapies and mapping shared cellular mechanisms among rare disorders, Encore aims to deliver actionable therapeutic leads for patients while establishing an open-access platform and database for the broader scientific community.
Stay tuned here for project updates!
Interested in joining this effort? We are actively looking for talented postdoctoral researchers excited about experimental or computational work at the intersection of functional genomics, rare disease biology, imaging, and machine learning. If you are excited about leveraging cutting-edge technology to accelerate precision medicine for rare diseases, please send a cover letter and current CV!