Embryo and fetal gene editing: Technical challenges and progress toward clinical applications

Abstract

Gene modification therapies (GMTs) are slowly but steadily making progress toward clinical application. As the majority of rare diseases have an identified genetic cause, and as rare diseases collectively affect 5% of the global population, it is increasingly important to devise gene correction strategies to address the root causes of the most devastating of these diseases and to provide access to these novel therapies to the most affected populations. The main barriers to providing greater access to GMTs continue to be the prohibitive cost of developing these novel drugs at clinically relevant doses, subtherapeutic effects, and toxicity related to the specific agents or high doses required. In vivo strategy and treating younger patients at an earlier course of their disease could lower these barriers. Although currently regarded as niche specialties, prenatal and preconception GMTs offer a robust solution to some of these barriers. Indeed, treating either the fetus or embryo benefits from economy of scale, targeting pre-pathological tissues in the fetus prior to full pathogenesis, or increasing the likelihood of complete tissue targeting by correcting pluripotent embryonic cells. Here, we review advances in embryo and fetal GMTs and discuss requirements for clinical application.

Graphical abstract

Abstract

Mattar and colleagues discuss how embryo and fetal editing represent paradigm shifts in hereditary disease management. Embryo editing, useful for understanding embryogenesis, has higher translational barriers than fetal editing with its appreciable benefits. Long-term effects of both must be studied to determine safety and efficacy, including germline transmission and genotoxicity.