A primary limitation in drug discovery is the lack of good model systems and this is especially true for neurodegenerative diseases such as ALS, Myasthenia Gravis, Charcot-Marie-Tooth Disease, and Alzheimer’s. Examples will be given of human-on-a-chip systems being developed for these CNS and PNS diseases, one that has enabled a clinical trial (#NCT04658472) that has now proceeded to a two-arm Phase III (NCT06290141 and NCT06290128).

Animal model reliance is a cornerstone of drug discovery and development. For rare diseases, extensive animal testing is required to create and validate models. This ethical and financial burden curtails rare disease research. We present a neuromuscular junction MPS to study Charcot-Marie-Tooth Disease Type 2S caused by a rare IGHMBP2 variant. This patient-specific in vitro model circumvented the need for animal model testing while providing the most representative disease model.

This talk discusses the utilization of neuromuscular models for evaluating disorders such as complement-mediated neuromuscular junction damage, myotonic dystrophy, and immune-related responses. The models are used to assess efficacy of various therapeutic modalities with clinically relevant and functional endpoints. The importance of baseline characterization and validation using detailed analysis of healthy and diseased cellular inputs before progressing to complex neuromuscular in vitro models will be highlighted.

Opal Therapeutics is advancing drug discovery in women’s health through the development of patient-derived endometrial and myometrial organoid models. These 3D cultures closely mimic the structure and function of the human uterine lining and muscle, providing a physiologically relevant system for studying reproductive disorders such as endometriosis and fibroids. By capturing patient-specific variability and disease phenotypes, Opal’s platform enables high-throughput drug screening and mechanistic studies with greater translational relevance than traditional rodent or 2D cell models. This approach offers a powerful new path to identify, validate, and optimize therapeutic candidates targeting chronic gynecological diseases with high unmet clinical need.

A decade ago our laboratory started a major transition towards using primary cells in support of drug discovery programs for autoimmune and inflammatory diseases. Donor to donor variability was a major concern at the outset. With now >25 primary cell assays developed and employed for SAR and HTS, sufficient data has been accumulated to conduct a meaningful analysis of these assays in high throughput pharmacology. Analysis results will be presented – including an answer to the title’s question - along with specific lessons and strategies gathered along the way to facilitate the use of these physiologically relevant assays.

In our pioneering, yet-to-be-published work, we construct a physiologically relevant ex vivo colorectal cancer (CRC) interface, unveiling two groundbreaking findings. Firstly, we establish that it is the oxygen gradient—not merely the absolute oxygen levels—that dictates CRC proliferation and architecture. Furthermore, this model facilitates an exploration into how these hypoxic gradients enable novel studies on epithelial-microbiota cocultures and tumor-T cell interactions.

The RosetteArray platform enables quantitative high-throughput screening of human neurodevelopment in standard well plate formats. By combining microarrayed, human pluripotent stem cell-derived neural organoid culture with AI-based image analysis, the effects of chemical/drug exposures and/or patient-specific genetic backgrounds on organoid morphogenesis can be screened in weeks versus months. Here, we demonstrate the utility of forebrain and spinal cord RosetteArray screens for developmental neurotoxicity hazard assessment and modeling Neural Tube Defect and Autism Spectrum Disorder risk factors.