Ethical considerations of preconception and prenatal gene modification in the embryo and fetus.

The National Academies of Sciences and Medicine 2020 consensus statement advocates the reinstatement of research in preconception heritable human genome editing (HHGE), despite the ethical concerns that have been voiced about interventions in the germline, and outlines criteria for its eventual clinical application to address monogenic disorders. However, the statement does not give adequate consideration to alternative technologies. Importantly, it omits comparison to fetal gene therapy (FGT), which involves gene modification applied prenatally to the developing fetus and which is better researched and less ethically contentious. While both technologies are applicable to the same monogenic diseases causing significant prenatal or early childhood morbidity, the benefits and risks of HHGE are distinct from FGT though there are important overlaps. FGT has the current advantage of a wealth of robust preclinical data, while HHGE is nascent technology and its feasibility for specific diseases still requires scientific proof. The ethical concerns surrounding each are unique and deserving of further discussion, as there are compelling arguments supporting research and eventual clinical translation of both technologies. In this Opinion, we consider HHGE and FGT through technical and ethical lenses, applying common ethical principles to provide a sense of their feasibility and acceptability. Currently, FGT is in a more advanced position for clinical translation and may be less ethically contentious than HHGE, so it deserves to be considered as an alternative therapy in further discussions on HHGE implementation.