Genome Editing Technologies: Defining a Path to Clinic

Abstract

R ecently developed genomic editing technologies have the potential to be powerful tools for gene therapy because of their ability to inactivate genes, correct mutated sequences, or insert intact genes. While the genomic editing field is advancing at an exceptionally rapid pace, there remain key issues regarding development of appropriate preclinical assays to evalu-ate off-target effects and establish safety. In order to begin a dialogue on these issues, the National Institutes of Health (NIH) Office of Science Policy, in collaboration with several NIH-funded investigators and the NIH Recombinant DNA Advisory Committee, organized a workshop on 10 June 2014, in Bethesda, Maryland, to provide a forum to educate the scientific and oversight communities and the public on different genome editing technologies, clinical experiences to date, and the preclinical assays being developed to examine the precision of these tools and their suitability for clinical application.Targeted genome modification by designer nucleases is an emerging technology that can be used to investigate gene function and could also be used to treat genetic or acquired diseases. A wide range of genome alterations has been achieved by these nucleases, including localized mutagenesis, local and dispersed sequence replacements, large and small insertions and deletions, and even chromosomal translocations. The nuclease approach to targeted genome editing has been applied successfully to more than 50 different organisms, including crop plants, livestock, and humans. 1 Recently developed genome editing technologies such as zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), meganucleases, and clustered regularly interspaced short

Genetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease

“…In the end, investigators need to maintain humility that any laboratory safety testing will likely be incompletely predictive of in vivo behavior of modified cells in humans. 153 As with all novel therapeutic approaches, meticulous clinical trials will be essential to ensure the success and safety of genetic approaches to SCD.…”

Ethical and regulatory aspects of genome editing

“…4,5 Although these technologies offer the potential for generation of transformative therapies for patients suffering from myriad disorders of hematopoiesis, their application for therapeutic modification of primary human cells is still in its infancy. Consequently, development of ethical and regulatory frameworks that ensure their safe and effective use is an increasingly important consideration.…”

Risk associated with off-target plant genome editing and methods for its limitation

“…The potential for adverse effects of off-target editing within the genome have been of intense interest to genome editing for human therapeutic applications where a key consideration is characterizing the occurrence of off-target edits on a genome-wide basis, since off-target edits could lead to adverse effects such as cytotoxicity, genotoxicity, or potential chromosomal rearrangements [20]. Unlike therapeutic applications in the cellular and mammalian system, where these potential adverse effects have direct implications to the treatment outcome, any toxic effects in plants are largely a technical challenge for accomplishing the genome edit.…”