Clinical OMICS

SEP-OCT 2018

Healthcare magazine for research scientists, labs, pathologists, hospitals, cancer centers, physicians and biopharma companies providing news articles, expert interviews and videos about molecular diagnostics in precision medicine

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www.clinicalomics.com September/October 2018 Clinical OMICs 35 Bradley and colleagues do not mince words on how signif- icant their findings may be for the future of CRISPR-based human gene-editing applications. Extensive on-target genomic damage may have "pathogenic consequences," the authors stated in the paper. Moreover, they stated that "in the clinical context of edit- ing many billions of cells, the multitude of different muta- tions generated makes it likely that one or more edited cells in each protocol would be endowed with an important pathogenic lesion." Bradley even invoked the disastrous results from some of the early gene-therapy trials about 15 years ago, when the accidental activation of the gene LMO2 by pro-viral insertion led to cases of cancer. 'Extraordinary Overstatement' However, some experts such as Fyodor Urnov, Ph.D., asso- ciate director at Altius Institute for Biomedical Sciences in Seattle and a pioneer of genome editing, feel that claiming "pathogenic consequences" is an "extraordinary overstate- ment" and said that the results were not altogether surpris- ing. Gaétan Burgio, M.D., Ph.D., group leader at The John Curtin School of Medical Research, Australian National University, noted that the occurrence of larger deletions from DNA breaks has been known within the field for some time. But he says the paper is significant because it is "the first comprehensive study investigating complex rearrange- ments after CRISPR editing. What is unusual here is the rate of the rearrangements (up to 25%), which is remarkable." Andrew Marshall, Ph.D., chief editor at Nature Biotechnol- ogy, agreed with Burgio that the results are not a complete surprise. "Although the findings are unexpected they are not completely unprecedented," he said, citing as an exam- ple a 2017 report in Nature Communications ("CRISPR/Cas9 targeting events cause complex deletions and insertions at 17 sites in the mouse genome" by Shin et al). Marshall said the ramifications of the Bradley report "could be large for the CRISPR research community working on human cells and in particular for companies developing CRISPR reagents as therapeutic modalities. Large dele- tions and rearrangements have the potential to affect neighboring genes, regu- latory elements, or even distal genes (in the case of rearrangements), adding another layer of complexity for clinical applications of genome editing." The report will naturally add to the scrutiny of a number of biotech com- panies hoping to advance CRISPR into the clinic. "A little bit alarmist" was how Tom Barnes, Ph.D., senior VP, innovative sciences at Intellia Therapeutics, a publicly traded biotech company commercializing thera- peutic applications of CRISPR gene editing, characterized how the new report was written. Taking the results in stride, Barnes noted that the new findings are "not new and not CRISPR-Cas9 specific." Echo- ing a similar sentiment, a spokesperson for Editas Medicine added that "we are aware of, and not specifically concerned about, this latest bench research finding as we work to make CRISPR-based medicines" and that "we've been thinking about this topic all along." Bradley, it should be noted, is one of the pioneers of gene targeting technology in mice dating back more than two decades and was the director of the U.K.'s flagship genome research center, the Wellcome Trust Sanger Institute, from 2001–2010. Michael Kosicki, of the Wellcome Sanger Institute and the first author on the paper, introduced Cas9 and guide RNA (gRNA) constructs targeting intronic and exonic sites of a gene called PIGA into mouse embryonic stem (ES) cells, both of which resulted in PIGA-deficient cells. Interestingly, when Kosicki and colleagues specifically targeted sites that were located in introns, hundreds of bases away from the PIGA coding region in areas where mutations would not be expected to cause a problem in function, they still recovered PIGA-deficient cells. When they amplified and sequenced a large region of the target area from pools of cells, they observed "a depletion of read coverage on a kilobase-scale around the cut sites, consistent with the presence of large deletions." To confirm Allan Bradley, Ph.D., of the Wellcome Sanger Institute, a lead author of the study, noted that extensive on-target genomic damage induced by CRISPR-Cas9 gene editing may have "patho- genic consequences." (continued on next page) "A focus on safety of experimental therapeutics is a central one for all who actually advance editing to the clinic." —Fyodor Urnov, Ph.D., Altius Institute for Biomedical Sciences

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