A New Induction to the Gene and Cell Therapy Hall Of Fame: Genome Editing

Abstract

The gene and cell therapy (GCT) family is inducting a new member. Following in the footsteps of viral gene transfer, nonviral gene transfer, RNA interference, oncolytic virotherapy, aptamers, and oligonucleotide therapeutics, targeted genomic interventions are about to transition from chemistry and preclinical modeling to clinical application. The ability to selectively target nucleases to chosen locations in the human genome, which has been bolstered by the discovery of meganucleases, zinc-finger proteins, TALENs (transcription activator-like effector nucleases), and, most recently, CRISPR/Cas9, is now reaching efficiencies that allow us for the first time to contemplate their medical use. The safety of such interventions remains to be further evaluated. Homologous recombination (HR) following transfection of large, homologous DNA templates, has long been used to introduce specific modifications in the genome of mammalian cells including embryonic stem cells. The pioneering work of Mario Capecchi, Martin Evans, and Oliver Smithies was recognized by the Nobel committee in 2007.1Nobelprize.org. The Nobel Prize in Physiology or Medicine 2007 http://www.nobelprize.org/nobel_prizes/medicine/laureates/2007Google Scholar However, this procedure was far too inefficient for practical use in primary cells. The demonstration that a double-strand break could greatly increase the probability of effective HR at the break site in mammalian cells2Rouet P Smith F Jasin M Expression of a site-specific endonuclease stimulates homologous recombination in mammalian cells.Proc Natl Acad Sci USA. 1994; 91: 6064-6068Crossref PubMed Scopus (470) Google Scholar paved the way for targeting nucleases to a sequence of interest. Formidable advances in the design of targeted nucleases and nickases have brought us a wealth of tools to catalyze HR and nonhomologous end-joining (NHEJ) in primary cells. We can now choose from several enzymes and DNA repair pathways to remodel the human genome. Owing to their relatively facile design, TALENS and the CRISPR/Cas9 system have unleashed broad use of these technologies, facilitating gene editing in plant, bacterial, and animal research. Moreover, these technologies now enable scientists and physicians to dream of specifically disrupting coding or noncoding sequences, targeting gene addition to a chosen location (such as a genomic safe harbor), and repairing harmful mutations, in a range of pathologies. These technologies, like any other, have their limits. Perfect gene repair occurs only in S and G2 phases, whereas NHEJ can occur throughout the cell cycle and is thus the more frequent outcome of DNA-repair reactions. This is adequate for gene disruption but not for mutation repair. Efficient repair of the sickle mutation in adult hematopoietic stem cells, for example, remains an elusive goal. Because targeted nucleases are not absolutely site-specific, they can cause off-target effects, including small genetic alterations that are more difficult to track and quantify than larger ones. The risk of such occult mutagenesis cannot be lightly discounted. Although the safety and efficacy of introducing such powerful enzymes in human cells—whether using DNA, messenger RNA, or protein—still need to be studied and optimized, a pathway to the clinic is clearly emerging.3Corrigan-Curay J O'Reilly M Kohn DB Cannon PM Bao G Bushman FD et al.Genome editing technologies: defining a path to clinic.Mol Ther. 2015; 23: 796-806Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar Gene editing holds great promise for advancing the treatment of inherited genetic disorders, infectious diseases, degenerative disorders, autoimmunity, and cancer. The genetic editing of T lymphocytes, to establish resistance to HIV or broaden the scope of T-cell engineering for cancer immunotherapy, is a likely vehicle to usher these technologies into the clinic before more challenging cell types can be tackled. The ASGCT is the natural home for nurturing and supporting advances in genome editing, as it has already done for all other GCTs. From viral vectors to aptamers and oncolytic viruses, the ASGCT has fostered advances in GCT since its establishment in 1996 under the leadership of George Stamatoyannopoulos. The Society's experience in basic biology, vector and cell manufacturing sciences, preclinical modeling, biosafety testing, regulatory development, first-in-human clinical trial design, molecular monitoring, ethics,4Friedmann T Jonlin EC King NM Torbett BE Wivel NA Kaneda Y et al.ASGCT and JSGT Joint Position Statement on Human Genomic Editing.Mol Ther. 2015; 23: 1282Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar and commercialization will now serve to guide and assist the scientific and medical application of gene editing to overcome biological and clinical challenges and enable its full deployment. The upcoming annual meeting of the ASGCT, on 4–7 May 2016 (http://www.asgct.org/meetings-educational-programs/asgct-annual-meetings/2016-annual-meeting), will again extensively feature gene editing research, including a special symposium on the safety and ethics of gene editing to be held 4 May (http://asgct.execinc.com/edibo/AM16GeneEditingWorkshop). This special issue on the topic of genome editing, which was developed and organized by Guest Editor Joe Kaminski and the Executive Editor, Robert Frederickson, illustrates the commitment of ASGCT and its flagship official journal, Molecular Therapy, to supporting genome editing research for the advancement of gene and cell therapies.