New CRISPR tool could tackle a plethora of genetic diseases
The system allows researchers more control over DNA changes, opening up conditions that have challenged gene-editorsEuropost
For all the ease with which the wildly popular CRISPR-Cas9 gene-editing tool alters genomes, it’s still somewhat prone to errors and unintended effects. A recently developed alternative, however, claims to offer greater control over genome edits - an advance that could be particularly important for developing gene therapies.
The alternative method, called prime editing, improves the chances that researchers will end up with only the edits they want, instead of a mix of changes that they can’t predict. The tool, described in a study published on 21 October in Nature, also reduces the ‘off-target’ effects that are a key challenge for some applications of the standard CRISPR-Cas9 system, making prime-editing-based gene therapies safer for use in people.
Most importantly, the tool seems capable of making a wider variety of edits, which might one day allow it to be used to treat the many genetic diseases that have so far stymied gene-editors. David Liu, a chemical biologist at the Broad Institute of MIT and Harvard in Cambridge, Massachusetts and lead study author, estimates that prime editing might help researchers tackle nearly 90% of the more than 75,000 disease-associated DNA variants listed in ClinVar, a public database developed by the US National Institutes of Health. The specificity of the changes that this latest tool is capable of could also make it easier for researchers to develop models of disease in the laboratory and study the function of specific genes.
“It’s early days, but the initial results look fantastic,” Brittany Adamson, who studies DNA repair and gene editing at Princeton University in New Jersey, told Nature. “You’re going to see a lot of people using it.”
CRISPR-Cas9 and prime editing both work by cutting DNA at a specific point in the genome. CRISPR-Cas9 breaks both strands of the DNA double helix and then relies on the cell’s own repair system to patch the damage and make the edits. But that repair system is unreliable and can insert or delete DNA letters at the points where the genome was cut. This can lead to an uncontrollable mixture of edits that vary between cells.
In addition, even when researchers include a template to guide how the genome is edited, the DNA repair system in most cells is far more likely to make those small, random insertions or deletions than to add a specific DNA sequence to the genome. That makes it difficult - and in some cases, nearly impossible - for researchers to use CRISPR-Cas9 to overwrite one piece of DNA with a sequence of their choosing.
Prime editing bypasses these problems. Although it also uses Cas9 to recognize specific DNA sequences - just like CRISPR–Cas9 does - the Cas9 enzyme in the prime editing tool is modified to nick only one DNA strand. Then, a second enzyme called reverse transcriptase and guided by a strand of RNA, makes the edits at the site of the cut.