© The American Society of Gene & Cell Therapy
editorial
doi:10.1038/mt.2016.25
A New Induction to the Gene and Cell
Therapy Hall Of Fame: Genome Editing
T
he gene and cell therapy (GCT) family is These technologies, like any other, have their
inducting a new member. Following in the limits. Perfect gene repair occurs only in S and G2
footsteps of viral gene transfer, nonviral gene phases, whereas NHEJ can occur throughout the
transfer, RNA interference, oncolytic virotherapy, cell cycle and is thus the more frequent outcome of
aptamers, and oligonucleotide therapeutics, targeted DNA-repair reactions. This is adequate for gene dis-
genomic interventions are about to transition from ruption but not for mutation repair. Efficient repair
chemistry and preclinical modeling to clinical ap- of the sickle mutation in adult hematopoietic stem
plication. The ability to selectively target nucleases cells, for example, remains an elusive goal. Because
to chosen locations in the human genome, which targeted nucleases are not absolutely site-specific,
has been bolstered by the discovery of meganucle- they can cause off-target effects, including small ge-
ases, zinc-finger proteins, TALENs (transcription netic alterations that are more difficult to track and
activator-like effector nucleases), and, most recently, quantify than larger ones. The risk of such occult
CRISPR/Cas9, is now reaching efficiencies that al- mutagenesis cannot be lightly discounted.
low us for the first time to contemplate their medical Although the safety and efficacy of introducing
use. The safety of such interventions remains to be such powerful enzymes in human cells—whether
further evaluated. using DNA, messenger RNA, or protein—still need
Homologous recombination (HR) following to be studied and optimized, a pathway to the clinic
transfection of large, homologous DNA templates, is clearly emerging.3 Gene editing holds great prom-
has long been used to introduce specific modifica- ise for advancing the treatment of inherited genetic
tions in the genome of mammalian cells including disorders, infectious diseases, degenerative disor-
embryonic stem cells. The pioneering work of Ma- ders, autoimmunity, and cancer. The genetic editing
rio Capecchi, Martin Evans, and Oliver Smithies of T lymphocytes, to establish resistance to HIV or
was recognized by the Nobel committee in 2007.1 broaden the scope of T-cell engineering for cancer
However, this procedure was far too inefficient for immunotherapy, is a likely vehicle to usher these
practical use in primary cells. The demonstration technologies into the clinic before more challenging
that a double-strand break could greatly increase the cell types can be tackled.
probability of effective HR at the break site in mam- The ASGCT is the natural home for nurturing
malian cells2 paved the way for targeting nucleases and supporting advances in genome editing, as it
to a sequence of interest. Formidable advances in has already done for all other GCTs. From viral vec-
the design of targeted nucleases and nickases have tors to aptamers and oncolytic viruses, the ASGCT
brought us a wealth of tools to catalyze HR and non- has fostered advances in GCT since its establish-
homologous end-joining (NHEJ) in primary cells. ment in 1996 under the leadership of George Stam-
We can now choose from several enzymes atoyannopoulos. The Society’s experience in basic
and DNA repair pathways to remodel the human biology, vector and cell manufacturing sciences,
genome. Owing to their relatively facile design, preclinical modeling, biosafety testing, regulatory
TALENS and the CRISPR/Cas9 system have un- development, first-in-human clinical trial design,
leashed broad use of these technologies, facilitating molecular monitoring, ethics,4 and commercializa-
gene editing in plant, bacterial, and animal research. tion will now serve to guide and assist the scientific
Moreover, these technologies now enable scientists and medical application of gene editing to over-
and physicians to dream of specifically disrupting come biological and clinical challenges and enable
coding or noncoding sequences, targeting gene ad- its full deployment. The upcoming annual meeting
dition to a chosen location (such as a genomic safe of the ASGCT, on 4–7 May 2016 (http://www.asgct.
harbor), and repairing harmful mutations, in a range org/meetings-educational-programs/asgct-annual-
of pathologies. meetings/2016-annual-meeting), will again exten-
Molecular Therapy vol. 24 no. 3 march 2016 407
© The American Society of Gene & Cell Therapy
editorial
sively feature gene editing research, including a special sympo- Michel Sadelain
sium on the safety and ethics of gene editing to be held 4 May President, ASGCT, and Member, Editorial Board
(http://asgct.execinc.com/edibo/AM16GeneEditingWorkshop).
This special issue on the topic of genome editing, which was REFERENCES
1. Nobelprize.org. The Nobel Prize in Physiology or Medicine 2007 <http://www.nobel-
developed and organized by Guest Editor Joe Kaminski and the prize.org/nobel_prizes/medicine/laureates/2007>.
Executive Editor, Robert Frederickson, illustrates the commit- 2. Rouet, P, Smith, F and Jasin, M (1994). Expression of a site-specific endonuclease
stimulates homologous recombination in mammalian cells. Proc Natl Acad Sci USA 91:
ment of ASGCT and its flagship official journal, Molecular Thera- 6064–6068.
py, to supporting genome editing research for the advancement of 3. Corrigan-Curay, J, O’Reilly, M, Kohn, DB, Cannon, PM, Bao, G, Bushman, FD et al.
(2015). Genome editing technologies: defining a path to clinic. Mol Ther 23: 796–806.
gene and cell therapies. 4. Friedmann, T, Jonlin, EC, King, NM, Torbett, BE, Wivel, NA, Kaneda, Y et al. (2015). AS-
GCT and JSGT Joint Position Statement on Human Genomic Editing. Mol Ther 23: 1282.
408 www.moleculartherapy.org vol. 24 no. 3 march 2016
