Abstract

The move from reading to writing the human genome offers new opportunities to improve human health. The United States National Institutes of Health (NIH) Somatic Cell Genome Editing (SCGE) Consortium aims to accelerate the development of safer and more-effective methods to edit the genomes of disease-relevant somatic cells in patients, even in tissues that are difficult to reach. Here we discuss the consortium’s plans to develop and benchmark approaches to induce and measure genome modifications, and to define downstream functional consequences of genome editing within human cells. Central to this effort is a rigorous and innovative approach that requires validation of the technology through third-party testing in small and large animals. New genome editors, delivery technologies and methods for tracking edited cells in vivo, as well as newly developed animal models and human biological systems, will be assembled—along with validated datasets—into an SCGE Toolkit, which will be disseminated widely to the biomedical research community. We visualize this toolkit—and the knowledge generated by its applications—as a means to accelerate the clinical development of new therapies for a wide range of conditions.

Highlights

  • Over the past few decades, a steady progression of techniques and technologies that enable user-programmable genome editing has been introduced, tested, improved and implemented

  • We outline the goals and strategies of the Somatic Cell Genome Editing (SCGE) Consortium, which has been established by the United States National Institutes of Health (NIH) to accelerate the development of solutions to many of these challenges

  • The most prominent genome-editing platforms (ZFNs, meganucleases, transcription activator-like effector nucleases (TALENs) and Cas9/Cas12a systems) relied almost exclusively on the realization[17] that the repair of nuclease-induced breaks in the genome can be exploited to induce genome edits (Fig. 1a)— either gene knockouts (through insertions or deletions generated by non-homologous end joining (NHEJ) or microhomology-mediated end-joining) or precise correction through homology-directed repair (HDR)[18]

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Summary

Introduction

Over the past few decades, a steady progression of techniques and technologies that enable user-programmable genome editing has been introduced, tested, improved and implemented. The development of methods to detect unwanted genomic events with increased predictive ability and sensitivity, as well as human cell and tissue systems such as organoids, are important components of the SCGE program. In addition to the discovery of new CRISPR–Cas systems, we will continue to develop and improve engineered platforms—for example, base editing21—that efficiently edit genomes, including in post-mitotic cells and in mitochondrial DNA24.

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