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      Responsible Translational Pathways for Germline Gene Editing?

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          Abstract

          Purpose of Review

          Continued development of gene editing techniques has raised the real possibility of clinical application of germline gene editing. These results, as well as reports of an unethical experiment which resulted in the birth of at least two children from edited embryos in 2018, have highlighted the urgency and importance of ethical issues about translational pathways for editing of human germline cells. Charting responsible translational pathways for germline gene editing requires tackling some significant and complex ethical issues.

          Recent Findings

          A literature on development of clinical applications of germline gene editing is emerging, and several key ethical issues are coming into focus as major challenges for responsible translational pathways.

          Summary

          Potential clinical utility, clinical justification, and human subjects research for germline gene editing raise outstanding ethical questions. Work on these questions will help provide guidance to researchers and clinicians and direct translational projects toward justifiable applications.

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          Most cited references58

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          Repair of double-strand breaks induced by CRISPR–Cas9 leads to large deletions and complex rearrangements

          CRISPR-Cas9 is poised to become the gene editing tool of choice in clinical contexts. Thus far, exploration of Cas9-induced genetic alterations has been limited to the immediate vicinity of the target site and distal off-target sequences, leading to the conclusion that CRISPR-Cas9 was reasonably specific. Here we report significant on-target mutagenesis, such as large deletions and more complex genomic rearrangements at the targeted sites in mouse embryonic stem cells, mouse hematopoietic progenitors and a human differentiated cell line. Using long-read sequencing and long-range PCR genotyping, we show that DNA breaks introduced by single-guide RNA/Cas9 frequently resolved into deletions extending over many kilobases. Furthermore, lesions distal to the cut site and crossover events were identified. The observed genomic damage in mitotically active cells caused by CRISPR-Cas9 editing may have pathogenic consequences.
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            Biotechnology. A prudent path forward for genomic engineering and germline gene modification.

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              Don't edit the human germ line.

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                Author and article information

                Contributors
                bcwik@pdx.edu
                Journal
                Curr Stem Cell Rep
                Curr Stem Cell Rep
                Current Stem Cell Reports
                Springer International Publishing (Cham )
                2198-7866
                21 August 2020
                : 1-8
                Affiliations
                GRID grid.262075.4, ISNI 0000 0001 1087 1481, Philosophy and University Studies, , Portland State University, ; Fourth Ave Building Suite 175, 1900 SW 4th Ave, Portland, OR 97201 USA
                Article
                179
                10.1007/s40778-020-00179-x
                7441015
                32844082
                d58acf7b-c012-4ab3-b358-03881ee5b47a
                © Springer Nature Switzerland AG 2020

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                Categories
                Genome Editing (Y Fan & J Chan, Section Editors)

                gene editing,germline,ethics,clinical utility,human subjects research,reproductive medicine

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