Multicellular Systems to Translate Somatic Cell Genome Editors to Humans

As genome editors move into clinical trials, there is a need to establish ex vivo multicellular systems to rapidly assess and predict toxic effects of genome editors in physiologically relevant human models. Advancements in organoid and organs-on-chip technologies offer the possibility to create multicellular systems that replicate the cellular composition and metabolic function of native tissues. Some multicellular systems have been validated in multiple applications for drug discovery and could be easily adapted to test genome editors; other models, especially those of the adaptive immune system, will require validation before being used as benchmarks for testing genome editors. Likewise, protocols to assess immunogenicity, to detect off-target effects, and to predict ex vivo to in vivo translation will need to be established and validated. This review will discuss key aspects to consider when designing, building, and/or adopting in vitro human multicellular systems for testing genome editors.