Scientists from Harvard University (Cambridge, MA, USA) have published a paper in the journal Nature, in which they present a new gene-editing method, which they have called “prime editing”, describing it as “a versatile and precise genome editing method that directly writes new genetic information into a specific DNA site”.
Although the well-known gene-editing tool CRISPR-Cas9 has been a revolution in the field of biomedical research (see HERE), the fact that its mechanism of action involves a cut in the DNA and its subsequent repair means that unwanted side effects are produced, obtaining modifications in the genome that are not the ones sought.
Prime editing tool
The new prime editing strategy is a further step in the refinement of gene editing. In this system, DNA breakage does not occur; rather, the “wrong letters” are changed to the right ones. Tools that follow this principle had already been developed previously, so-called “base editors”. These used a “dead” Cas9 enzyme, which was still able to bind DNA but did not cut it. Instead, it carried another enzyme to it that specifically changed one letter for another. The novelty of prime editing with respect to previous base editing systems is that the enzyme that binds to the “dead” Cas9 is an engineered reverse transcriptase (it generates DNA from RNA) which uses a prime RNA editing guide (pegRNA) that locates the editing site and, in turn, acts as a template to correct the mutation.
The scientist David Liu, lead author of the study, explains it thus to Diario Médico (Spanish journal of medicine): “If CRISPR is the scissors, the base editors would be the pencil: instead of cutting the double helix, they convert one letter of the DNA into another without breaking the double chain, which allows efficient correction of the main types of mutation, but not all. The ‘prime’ editor would be the ”find and replace” system of a word processor; it allows specific point mutations, insertions and deletions of a single letter, and combinations of these to be made, also without having to break the double chain”.
The accuracy of the prime editor system is such that, theoretically, it could correct nearly 89% of the genetic mutations associated with human diseases. In their paper, the researchers conclude that the prime editor offers significant advantages over the common CRISPR system since the efficiency and purity of the product are higher and largely avoid off-target effects.
Marc Güell, a researcher in Synthetic Biology at the Universitat Pompeu Fabra (UPF) – Barcelona, Spain, in statements to Diario Médico, says that “in addition to providing a robust method for correcting pathogenic alleles, it opens a large number of biotechnology possibilities. It allows minor alleles to be corrected with a higher level of certainty than previous methods and in a very wide range of conditions (including cells that do not divide a lot). It also appears to have a low level of off-target effects”. Güell considers that, although the classic CRISPR-Cas9 works very well “for breaking or inactivating genes”, the prime editor seems “quite superior for correcting” genetic errors. Furthermore, “it is potentially safer”, as it avoids breaking the double-stranded DNA. (Nature of the same date published an article titled Super-precise new CRISPR tool could tackle a plethora of genetic diseases, you can read HERE).
Bioethical assessment. Very positive development with possible ethical implications
From a bioethical point of view, this is a very positive development that could go beyond the already significant promises of CRISPR in gene therapy. As research in this field progresses, the safety of the method must be confirmed prior to its clinical application. On the other hand, the possibility of applying the technique in the human germline (gametes and embryos) would entail particular bioethical problems, most notably the production of human embryos in vitro, the destruction of thousands of them in experiments, and the risks of seriously affecting the early development of treated individuals.