Latest CRISPR therapy concern weighs on share prices

Professor Allan Bradley. (Wellcome Sanger Institute)

Yet another study warning of potential toxicity with the CRISPR/Cas9 gene-editing technique has hit the headlines, giving investors in CRISPR companies the jitters.

The latest research—published in the prestigious journal Nature Biotechnology—suggests that the DNA-cutting enzyme used to modify genes may cause undetected genetic changes that could have unwanted effects and make it harder to develop CRISPR-based therapies, some of which are due to start trials later this year.

The finding, which comes after earlier warnings about the safety of the technique, took a toll on the share prices of prominent CRISPR biotechs like CRISPR Therapeutics, Intellia Therapeutics, Sangamo, and Editas Medicine, which all fell after news of the findings broke.

In the study, a team of researchers co-led by Allan Bradley, a professor at the Wellcome Sanger Institute, found that in around a fifth of mouse and human cells tested deletions occurred that were far longer than expected, sometimes extending to hundreds or even thousands of base pairs that “may have pathogenic consequences.”

Research to date has focused on the immediate vicinity of the target site, but this is the first study to systematically look for large genetic rearrangements such as insertions and deletions (indels) across the genome. It found some occurring too far away from the target site to be seen with standard genotyping methods.

"We found that changes in the DNA have been seriously underestimated before now," said Bradley.“Anyone thinking of using this technology for gene therapy proceeds with caution and looks very carefully to check for possible harmful effects.”

It’s a worrying conclusion for a technology whose major claimed advantage is that it is both highly targeted and safe. The primary point of CRISPR-Cas9 is that it is supposed to cut DNA with exquisite precision at a target site, allowing specific and reproducible changes to be made while the cellular repair process kicks in.

In theory, that means it could be used therapeutically to disable or correct problem genes, but a lot of unexpected genetic changes could scupper its potential. Now, the authors of the latest study call for broader testing for unexpected changes before any potential therapies based on the technique are tested in humans.

“This study is the first to assess the repertoire of genomic damage arising at a CRISPR/Cas9 cleavage site,” according to Professor Maria Jasin, an independent researcher from Memorial Slone Kettering Cancer Centre, who wasn’t involved in the study.

“While it is not known if genomic sites in other cell lines will be affected in the same way, this study shows that further research and specific testing is needed before CRISPR/Cas9 is used clinically.”

Earlier warnings about safety focused on whether the gene-editing technique would actually increase the risk of cancer in some cells by switching off a mechanism that protects them from DNA damage.

And last month, the FDA placed a clinical hold on a CRISPR candidate for sickle cell disease in development at CRISPR Therapeutics and Vertex, delaying the start of its first human trial of the technology. No reasons for the delay have yet been disclosed.

Gene-editing drug developers said the findings were interesting but pointed out that side effects such as cancer haven’t been seen in preclinical studies in cells and animal models of CRISPR/Cas9 or indeed other, more established techniques techniques such as zinc finger nucleases and TALEN.