This is an example of how new drugs developed with the latest new technologies can lead to dangerous unintended side-effects that only become apparent later after many subjects have been “treated”.
When a new technology, like CRISPR gene editing, is used we cannot use past experience to assume anything and cannot predict results precisely because we’re doing something categorically different from before.
As CRISPR-Cas9 starts to move into clinical trials, a new study published in Nature Methods has found that the gene-editing technology can introduce hundreds of unintended mutations into the genome.
CRISPR-Cas9 editing technology — by virtue of its speed and unprecedented precision — has been a boon for scientists trying to understand the role of genes in disease. The technique has also raised hope for more powerful gene therapies that can delete or repair flawed genes, not just add new genes.
But even though CRISPR can precisely target specific stretches of DNA, it sometimes hits other parts of the genome.
Most studies that search for these off-target mutations use computer algorithms to identify areas most likely to be affected and then examine those areas for deletions and insertions
“These predictive algorithms seem to do a good job when CRISPR is performed in cells or tissues in a dish, but whole genome sequencing has not been employed to look for all off-target effects in living animals,” says co-author Alexander Bassuk, MD, PhD, professor of pediatrics at the University of Iowa.
The researchers determined that CRISPR had successfully corrected a gene that causes blindness, but Kellie Schaefer, a PhD student in the lab of Vinit Mahajan, MD, PhD, associate professor of ophthalmology at Stanford University, and co-author of the study, found that the genomes of two independent gene therapy recipients had sustained more than 1,500 single-nucleotide mutations and more than 100 larger deletions and insertions.
None of these DNA mutations were predicted by computer algorithms that are widely used by researchers to look for off-target effects.
Dr. Bassuk says the researchers didn’t notice anything obviously wrong with their animals. “We’re still upbeat about CRISPR,” says Dr. Mahajan.
“We’re physicians, and we know that every new therapy has some potential side effects–but we need to be aware of what they are.”
“We hope our findings will encourage others to use whole-genome sequencing as a method to determine all the off-target effects of their CRISPR techniques and study different versions for the safest, most accurate editing,” Dr. Tsang says.