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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36 Clinical OMICs September/October 2018 www.clinicalomics.com these results, the researchers isolated single-celled clones of CRISPR-Cas9 treated cells and used PCR to characterize the genomic region, confirming the presence of larger deletions and rearrangements. They also observed alleles in which the intronic gRNA caused an inversion of a region containing the exon. They go on to say that these would have been easy to miss if the assessment had been limited to the immediate vicinity of the cleavage site resulting in their phenotypic consequences being underestimated. Not so Fast Barnes said that nothing about the science being done at Intellia will change as a response to this finding, because they "have been aware of it and their current approaches are inclusive of this phenomenon." However, with these "CRISPR calamity" stories popping up routinely, he mentioned that "Intellia could be more upfront and more system- atic in describing their work. When we started, we worked out all of the pos- sible ways that this could go awry" and that "we've been out ahead of a lot of these problems," Barnes added. Urnov remarked that the Bradley paper "does not present any data in clini- cally relevant human cells, or nucleases engineered for clinical-grade use deployed in those cells using clin- ically relevant delivery modalities. Until such data are shown, it is impossible to tell." "A focus on safety of experimental therapeutics is a cen- tral one for all who actually advance editing to the clinic," Urnov added. But if the phenomenon described in the Brad- ley paper is observed in clinically relevant human cells, he said "there is no question that a way to address it will be found." Patrick Hsu, Ph.D., a principal investigator at the Salk Institute for Biological Studies, also looked to quell fears as "the large deletions found in this study are still in the sin- gle–digit kilobase range, so they are still mostly local events that may not necessarily affect neighboring genes." "CRISPR encompasses much more than double-stranded DNA breaks and error-prone repair," Hsu added. "Impor- tantly, other CRISPR-based platforms such as base edit- ing, transcriptional perturbation, or RNA targeting are not affected by these findings" because they do not rely on dou- ble-stranded DNA breaks. Not CRISPR-Cas9's First Time in the Hot Seat Over the past 15 months, CRISPR-Cas9 gene editing has been the topic of a series of reports raising potential safety concerns regarding the specificity, immunogenicity and tumorigenicity of the technology. In May 2017, Vinit Maha- jan's, M.D., Ph.D. group at Stanford University published a paper entitled "Unexpected mutations after CRISPR-Cas9 editing in vivo" in Nature Methods, which called the safety of CRISPR-Cas9 technology into question due to wide- spread off-target effects. That paper triggered a strong response from industry and academic researchers. In time, Maha- jan's group published a fol- low-up preprint in bioRxiv followed by a retraction of the original paper earlier this year. This drama was followed by two other scares; a pre- print from Matthew Porte- us's, M.D., Ph.D., group at Stanford University last Jan- uary that there are pre-ex- isting immune responses (both humoral and cell-mediated) to Cas9 in humans, suggesting that some individuals may be immune to CRISPR-Cas9 based therapies. More recently, a pair of papers in Nature Medicine suggested that selecting CRISPR-edited cells may also select for cells with a p53 mutation which could result in cancer. In regard to these potential challenges, Hsu said, "We won't necessarily know their relative importance until we are in the clinic. Overall, appropriately designed preclinical safety assays will need to be tailored for each gene–editing therapeutic that takes this into account." (continued from previous page) KEITH CHAMBERS/SCIENCE PHOTO LIBRARY / Getty Images

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