Genome Editing Technologies: Defining a Path to Clinic

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Presentation transcript:

Genome Editing Technologies: Defining a Path to Clinic Jacqueline Corrigan-Curay, Marina O'Reilly, Donald B Kohn, Paula M Cannon, Gang Bao, Frederic D Bushman, Dana Carroll, Toni Cathomen, J Keith Joung, David Roth, Michel Sadelain, Andrew M Scharenberg, Christof von Kalle, Feng Zhang, Robert Jambou, Eugene Rosenthal, Morad Hassani, Aparna Singh, Matthew H Porteus  Molecular Therapy  Volume 23, Issue 5, Pages 796-806 (May 2015) DOI: 10.1038/mt.2015.54 Copyright © 2015 American Society of Gene & Cell Therapy Terms and Conditions

Figure 1 Nuclease site recognition features. Zinc-finger nuclease dimer: recognition sites 9–18 bp × 2. (b) TAL effector nuclease (TALEN): recognition sites 12–20 bp × 2, spacer 12–20 bp. (c) RNA-guided endonuclease CRISPR/Cas9. Courtesy of Matthew Porteus Molecular Therapy 2015 23, 796-806DOI: (10.1038/mt.2015.54) Copyright © 2015 American Society of Gene & Cell Therapy Terms and Conditions

Figure 2 Mechanisms of DNA repair after targeted cleavage. HDR, homology-dependent repair; NHEJ, nonhomologous end joining. Courtesy of Dana Carroll. Molecular Therapy 2015 23, 796-806DOI: (10.1038/mt.2015.54) Copyright © 2015 American Society of Gene & Cell Therapy Terms and Conditions

Figure 3 Plots showing the relationship between concentration of a given nuclease and on-target vs. off target activity. A “good” nuclease should exhibit high specificity and affinity for its cognate binding site such that the mass action equilibrium will not shift in favor of off-target sites with small increases of nuclease concentrations. “Bad” nucleases with low specificity are prone to bind more off-target sites with small changes in nuclease concentration and thus limit the ability to reach an effective non-toxic dose. Courtesy of Toni Cathomen. Molecular Therapy 2015 23, 796-806DOI: (10.1038/mt.2015.54) Copyright © 2015 American Society of Gene & Cell Therapy Terms and Conditions