Right model, right complexity: using in vitro human disease cell models in drug discovery

Ensuring that drug candidates can reach the clinic is no easy task, so having models that can closely represent human pathology is crucial. Here, Dr Beth Hoffman, CEO of Origami Therapeutics, describes the successes and challenges of using human disease cell models in drug discovery.

Billions of dollars are spent annually in the development of promising new drugs to treat human disease, although greater than 75 percent fail before reaching Phase III clinical trials.1-3 In drug discovery and development, even the most promising candidates can fail to translate from pre-clinical disease models to efficacy and safety in clinical trials.3 As resources, time and cost increase at each phase, being able to employ pre‑clinical models that can closely predict clinical outcome as early as possible in the discovery process is vital. This includes having robust, reproducible in vitro disease models amenable to selecting the most promising candidates, at the correct scale and right stage of discovery.

Historically, the use of recombinant cell and rodent disease models has not translated to efficacy in clinical trials. Human cells have become more widely used for in vitro testing of promising new cancer therapies and potential drug candidates to address diseases affecting peripheral organs. For these conditions it is often possible to obtain patient biopsies or tissues from organ transplants from which primary cells can be isolated and cultured in vitro. Being patient-derived, these types of cells demonstrate the actual disease genotype and phenotype. These cells provide a relatively accurate in vitro disease model, notwithstanding changes to the cells that can occur upon extensive culturing, especially in two‑dimensions (2D) on a tissue culture plate.4 One particularly compelling example is human bronchial epithelial cells (HBEs) from cystic fibrosis (CF) patients’ lungs. These have been used to accurately predict efficacy of the CF drugs Kalydeco, Orkambi and Trikafta.5