APPLICATION OF NEXT GENERATION TECHNOLOGIES: EP.321 Revolutionizing drug discovery in genetically-defined muscle disease using single-cell and high dimensional datasets

Abstract

Our vision at fulcrum therapeutics is to transform the future of patients living with genetically-defined diseases. Our approach to drug discovery avoids the pitfalls that have plagued our industry and harnesses recent technological advances that allow us to forge a new path for patients. Using the latest advances in single cell methods, we can look deeper into diseased tissue to generate powerful insights into the drivers of disease and identify new ways to re-balance the cellular composition and dysregulation of pathological microenvironments. Our fulcrumseek platform brings together the deep understanding of tissue biology elucidated from the hypothesis-generating combination of snRNA-seq and spatial transcript/proteomics studies of human samples, with the latest technologies in cellular modeling and comprehensive phenotypic screening using high-throughput RNA-seq and high content imaging. We are applying the power of machine learning together with the creative and inventive spark of human intelligence to unravel the richness of this data and revolutionize drug discovery in muscular dystrophies. Using this approach, we have characterized biopsies from dystrophic muscle to understand the cellular composition, interactions, and processes that drive muscle degeneration and loss of function. Now, we are creating a database of cellular profiles generated in response to our highly curated and annotated chemical library and functional genomics tools to identify novel targets that can modulate these drivers of disease. Here, we demonstrate that by applying this integrated target discovery approach in FSHD patient biopsies as well as patient-derived myotubes in vitro, we can rapidly rediscover previously known targets in FSHD, as well as identifying novel targets. This platform has the potential to fundamentally change the way drugs are discovered and developed for patients with devastating muscle diseases.