Newly designed synthetic molecules that can edit DNA without making a cut, can successfully correct mutations in the blood disorder β-thalassemia in mice
Gene editing has phenomenal potential but there are many deficiencies and concerns over current systems and techniques, which has led to ongoing efforts to create refined or alternative systems that overcome these challenges.
A gentler form of editing
In a new study outlined in Nature Communications, researchers have successfully used synthetic molecules consisting of a protein-nucleic acid blend to edit mutations in live mice. The new ‘PNA’ system is unusual in that it doesn’t cut DNA to alter the sequence. Instead it opens up the conjoined double strand and creates a triple helix – leaving one strand unbound and initiating the cell’s own mechanisms to change the targeted bases. This reduces risk of unwanted, off-target snips which could cause serious side effects.
“We have developed a system that uses FDA-approved nanoparticles to deliver our PNA molecule along with a donor DNA to repair a malfunctioning gene in living mice. This has not been achieved with CRISPR”
A promising method
The innovative system was packaged within nanoparticles for widespread delivery, alongside a healthy donor strand (in this case for hemoglobin subunit β, which is used as a template to correct the mutated strand) and an additional factor that enhances the correction process. The PNA was produced using an advance that attached a polyethylene glycol group – keeping the molecules water soluble and preventing it from non-specific binding. It also shifted the shape of the PNA into a right handed helix to make it more compatible with DNA.
The efficiency level appeared to hover around 7%, which is a significant improvement upon previous approaches which are closer to 0.1% efficiency. This bodes well for disease correction, as research shows often a small rate of correction is enough to effectively cure a number of diseases.
“The effect may only be 7%, but that’s curative. In the case of this particular disease model, you don’t need a lot of correction. You don’t need 100% to see the phenotype return to normal”
Another advantage of the system is that it’s much smaller and easier to deliver, which is a big barrier with CRISPR. Enzymes are comparatively large, but this PNA bundle can be delivered with efficiency nanoparticles in a living organism.
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