Research published Monday in the journal Nature Biotechnology suggests that gene editing using CRISPR-Cas9 can cause more genetic damage in cells than was previously thought. The findings come after work from a pair of studies  recently published in Nature Medicine linked the CRISPR-Cas9 gene-editing system to an increased risk of cancer in certain cells.
Scientists involved in the latest work noted that so far, "exploration of Cas9-induced genetic alterations has been limited to the immediate vicinity of the target site and distal off-target sequences, leading to the conclusion that CRISPR–Cas9 was reasonably specific." However, after conducting a full systematic study in both mouse and human cells, they discovered "significant on-target mutagenesis, such as large deletions and more complex genomic rearrangements at the targeted sites in mouse embryonic stem cells, mouse haematopoietic progenitors and a human differentiated cell line."
Specifically, the frequency of large deletions in the human cells that were analysed, derived from a retinal pigment epithelial cell line, ranged from 3 percent to 9 percent, whereas in the mouse cells, which were the main focus of the study, the rate was up to 20 percent. The researchers noted that the large genetic rearrangements, including DNA deletions and insertions, could lead to important genes being activated or repressed. Moreover, some of the changes were too far away from the target site to be seen with standard genotyping methods, they added.
Corresponding author Allan Bradley remarked "this is the first systematic assessment of unexpected events resulting from CRISPR-Cas9 editing in therapeutically relevant cells," adding that "it is important that anyone thinking of using this technology for gene therapy proceeds with caution, and looks very carefully to check for possible harmful effects."
Gene editing companies such as Editas Medicine, CRISPR Therapeutics and Intellia Therapeutics saw their shares fall as much as 5 percent to 7 percent shortly after the paper was published.
Tom Barnes, senior vice president of innovative sciences at Intellia, pointed out that researchers in the study only examined a few types of cells, including actively dividing cells, whose DNA gene editing is known to delete larger chunks of, while Intellia is targeting quiescent cells that display smaller deletions. He also said Intellia has not observed such large-scale deletions in the cells it is targeting, including liver cells. "This [paper] doesn't cause us to change anything we're doing," Barnes stated.
Meanwhile, an Editas Medicine spokesperson remarked that company scientists "do not believe [the issue] is specifically problematic in our work to make CRISPR-based medicines."