Stem Cell Reports Forum Ethics and regulatory considerations for the clinical translation of somatic cell human epigenetic editing Nikolajs Zeps, 1 Tamra Lysaght, 2, * Ruth Chadwick, 3 Alexandre Erler, 4,10 Roger Foo, 5,8 Simona Giordano, 6 Poh San Lai, 7 G. Owen Schaefer, 2 Vicki Xafis, 2 Wei Leong Chew, 8 and Jeremy Sugarman 9 1 Eastern Health Clinical School, Monash University, Melbourne, VIC, Australia 2 Centre for Biomedical Ethics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore 3 School of Social Sciences, Cardiff University, Cardiff, UK 4 CUHK Centre for Bioethics, Chinese University of Hong Kong, Hong Kong, China 5 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore 6 School of Law, University of Manchester, Manchester, UK 7 Department of Paediatrics, National University of Singapore, Singapore, Singapore 8 Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore 9 Berman Institute of Bioethics, Johns Hopkins University, Baltimore, MA, USA 10 Philosophy Department, Chinese University of Hong Kong, Hong Kong, China *Correspondence: tlysaght@nus.edu.sg https://doi.org/10.1016/j.stemcr.2021.06.004 Altering the human epigenome with gene-editing technology in attempt to treat a variety of diseases and conditions seems scientifically feasible. We explore some of the ethical and regulatory issues related to the clinical translation of human epigenetic editing arguing that such approaches should be considered akin to somatic therapies. INTRODUCTION DNA methylation is one mechanism of epigenetic regulation of gene expression and variations in the methylation of the promoter regions of genes are associated with a variety of human diseases. The discovery and application of the CRISPR-Cas gene-editing system has created new opportunities not only for using it to manipulate genomes for therapeutic purposes (Pickar-Oliver and Gersbach 2019), but also to develop therapeutic modalities through methylation-spe- cific epigenome modification (Gjal- tema and Rots 2020). Although there is substantial ongoing debate around human genome editing, especially of the germline, there has been relatively little discussion of the ethics and regu- lation of human epigenome editing (e-GE) of somatic cells using this technology. There are currently no human trials using e-GE registered in ClinicalTrials. gov , but there are a number of preclin- ical approaches moving toward human testing in the near future (Hirakawa et al., 2020). Given the tangible possi- bility of ameliorating a variety of dis- eases and conditions with e-GE (Table 1), it is critical to examine the related ethical and regulatory issues. To do so, we first address issues related to possible unwanted effects of somatic cell e-GE on the germline. Next, we examine three broad plausible ap- proaches to the clinical translation of somatic cell e-GE: (1) targeting disease genes; (2) augmenting existing thera- pies; and (3) enhancing phenotypic traits. We then describe some of the sci- entific and ethical uncertainties of these approaches and their implica- tions. Finally, we discuss some associ- ated regulatory issues. Unwanted effects of e-GE on germ cells One of the primary concerns with changes to germ cells is that delete- rious changes could be potentially passed on to future generations, for whom germline changes would be irreversible. Such germline modifica- tions are therefore typically unwanted for somatic editing in general, and e- GE in particular. While a comprehensive scientific re- view of human e-GE is beyond the scope of this Forum, it is important to note that several lines of evidence sug- gest that it is unlikely to result in changes that lead to enduring germline effects. First, current evidence suggests that e-GE is unlikely to change the un- derlying genetic DNA sequence of cells (Gjaltema and Rots 2020). Second, given global resetting of the methyl- ation state in the embryo, inheritable epigenetic modification is unlikely to manifest in offspring. Third, environ- mentally induced epigenetic modifica- tion is transitory and can be reversed by further environmental changes, and is the basis for related recommen- dations about altering lifestyle and exposure to environmental factors in relation to methylation-based alter- ations in gene expression related to the development of cancer. Fourth, contemporary approaches to e-GE may only result in transient changes in target cells (Zezulin and Musunuru 2018). Thus, the lack of enduring germline effects of e-GE avoids some of the ethical concerns raised with human germline genome editing, which are not easily reversible, and where its effects will be passed onto future generations. Accordingly, e-GE of somatic cells ought instead to be considered akin to somatic cell and gene therapy rather than as Stem Cell Reports j Vol. 16 j 1–4 j July 13, 2021 j ª 2021 The Authors. 1 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Zeps et al., Ethics and regulatory considerations for the clinical translation of somatic cell human epige- netic editing, Stem Cell Reports (2021), https://doi.org/10.1016/j.stemcr.2021.06.004