Advances in genome editing technologies will beanother powerful tool available to scientists inJanssen R&D in their efforts to discover and develop safeand effective medicines.
By Inès Royaux, PhD
Senior Scientist at Janssen R&D
The ability to engineer precisely targeted much excitement due to its simplicity, modifications within the mammalian genome high efficiency, high speed, and low cost. using meganucleases, zinc-finger nucleases It has been widely acknowledged as a (ZFNs) or transcription activator-like (TAL) major breakthrough in biology and indeed effector nucleases (TALENs), has great potential many researchers including Janssen R&D for drug discovery and development. These immediately recognized the potential of first and second generation approaches have this groundbreaking technology. In 2014, advanced to the clinic and are currently in Emmanuelle Charpentier and Jennifer Doudna early stage human trials.
The technologies received the Dr. Paul Janssen Award for underlying both ZFNs and TALENs rely on Biomedical Research in recognition for their targeting specific genes within the genome discovery of this DNA editing strategy.“The using a protein-based recognition ‘cassette’work of Drs. Doudna and Charpentier has engineered to recognize and bind to a given the potential to make a significant impact genetic sequence. Highly precise gene on human health, which is the very heart targeting can be achieved but often requires of Dr. Paul Janssen’s legacy, as well as our complex protein engineering and intracellular mission at Johnson & Johnson.” said Paul delivery can be challenging. These limitations Stoffels MD, Chief Scientific Officer of Johnson have been a deterrent to the wide-scale & Johnson, the parent company of Janssen adoption of the technologies. Pharmaceuticals. Recently, the discovery of the CRISPR/An attractive aspect of the CRISPR approach Cas9 based genome editing has generated is the delivery via a lentiviral format for large-scale loss-of-function and gain-offunction screens, similar to the lentiviral shRNA platform. Through a partnership with the Broad Institute, the Functional Genomics Consortium (FGC), Janssen scientists are sing cutting-edge lentiviral CRISPR libraries for a variety of applications including for the potential to make a significant impact on humanidentification and validation of new drug targets in complex cellular systems. These health, which is the very heart of Dr. Paul Janssen’sinclude induced pluripotent stem (iPS) cell- derived neurons and intestinal organdies action or resistance to the rapeutics is critical for the discovery of promising new medicines. Exciting data has already been generated in proof-of-concept studies and ongoing experiments are expected to provide novel insights into the proteins and pathways involved in the invitation and progression of diseases of interest to Janssen R&D.
“The work of Drs. Doudna and Charpentier has the potential to make a significant impact on human health, which is the very heart of Dr.Paul Janssen’s legacy, as well as our mission at Johnson & Johnson”
Paul Stoffels MD
Chief Scientific Officer of Johnson & Johnson, the parent company of Janssen Pharmaceuticals.
While the initial focus within Janssen and other groups has been in the application of gene editing technologies for basic and translational research, a number of biotech and startup companies (many of then spun out from the original ground breaking work in academia) have begun exploring the therapeutic applications of genome editing in humans. Janssen has invested in exploratory studies in the therapeutic space by partnering with Poseida Therapeutics, a spinout of Transposagen, for the development of T-cell therapies based on adoptive transfer of chimeric antigen receptor (CAR) T-cells. In this collaboration, Poseida Therapeutics will deploy Transposagen’s latest technologies to reengineer T-cells by inactivating particular receptor genes and then expressing anartificial cell surface receptor to target cancer cells.
With this existing collaboration, Janssen is hoping to generate off-the-shelf therapy to treat and potentially cure cancers. Given the insights gained from the tremendous growth in the application of gene editing across a wide spectrum of research, it is now possible to choose from the different nuclease-based gene editing technologies the most appropriate tool for a particular application. For example in the case of iPSC engineering (where the goal is introduction of specific point mutations), Janssen has opted for the well validated ZFN-based gene editing tool. A series of isogenic MAPT mutant iPSC lines have already been generated and are being applied in disease modelling. However we note that while the protocols for executing these studies are well known, it is by no means simple or straight forward to apply them – experience and perseverance are additional critical ingredients! In conclusion, gene editing based on the ZFN, TALEN and CRISPR technologies have rapidly become indispensable tools in pharmaceutical research. They provide a means to rapidly model human disease in a way that was not possible before, and as such provide a transformational advance that will facilitate and catalyze the search for better therapies, as we keep in mind the quote of Dr. Paul Janssen, “the patients are waiting”.