The approval over the past decade of viral gene therapy and RNAi/antisense-based medicines for both genetic diseases and cancer has provided a comprehensive preclinical, regulatory, and commercial framework to advance a nucleic-acid-directed experimental therapy through first-in-human trials and to licensure. This paved the way for development of genome/gene editing approaches.

Following the 2012 discovery that programmable, RNA-directed nucleases such as Cas9 derived from CRISPR-based bacterial adaptive immune systems can be used for genome editing in mammalian cells, along with the continued development of editing platforms, progress toward moving these gene editing technologies to the clinic has accelerated. The full realization of the hope and promise of transformative therapies is on the horizon, and the coming decade will likely feature the approval of a number of gene editing-based medicines. While the challenge of engineering nuclease-based gene editing tools that evoke a desired genetic change at a given locus efficiently and specificity has largely been solved, the focus of the current effort and, accordingly, of this special issue of Molecular Therapy, is to illuminate the following: (i) approaches that do not require a double-stranded DNA break (DSB) to drive a desired genetic outcome; (ii) engineering more versatile, facile, and safe methods to deliver the genome editing machinery ex vivo and in vivo; (iii) developing ways to profile the on- and off-target activities of genome editing enzymes commensurate with the need to apply it to chronic rather than acute disease; (iv) establishing robust preclinical paths to advancing to first-in-human approaches for genome editing in vivo; (v) facilitating manufacture of the editing machinery and the resulting drug product; (vi) expanding the scope of clinical applications both to common disease (e.g., chronic pain and cardiovascular disease) and to ultrarare genetic conditions.

Invited reviews

Daniel E. Bauer
Boston Children’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School

Paula Cannon
Distinguished Professor in the Department of Molecular Microbiology & Immunology, University of Southern California, Keck School of Medicine

Katherine A. High
Emeritus Professor of Pediatrics, Perelman School of Medicine, University of Pennsylvania

David R. Liu
Thomas Dudley Cabot Professor of the Natural Sciences, Howard Hughes Medical Institute Investigator, Department of Chemistry and Chemical Biology, Harvard University

Crystal Mackall
Ernest and Amelia Gallo Family Professor and Professor of Pediatrics and of Medicine, Standford

Mitchell J. Weiss
Chairman, Department of Hematology, Arthur Nienhuis Endowed Chair in Hematology, St. Jude Children’s Research Hospital

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