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A team of researchers from the Massachusetts Institute of Technology (MIT) has developed a new generation of prime editors—gene editing tools designed to rewrite DNA with far greater accuracy. The study, led by Professor Phillip Sharp and published in Nature, addresses one of the biggest hurdles in prime editing: the risk of unwanted DNA changes known as insertions and deletions (indels). Unlike the traditional CRISPR-Cas9 system, which cuts both strands of DNA, prime editing makes a single-strand nick, but even this approach can lead to errors that limit its safety for cell and gene therapy applications.
To overcome this challenge, the team engineered modified versions of the Cas9 nickase enzyme to better control how DNA is cut and repaired. By introducing specific mutations that altered the enzyme’s nicking behaviour, they developed a precision prime editor (pPE) that reduced indel errors by 118-fold compared to the standard PEmax system. This was achieved by promoting controlled degradation of unstable DNA ends, which helped ensure that the desired edits were incorporated correctly.
Building on this success, the researchers further enhanced editing accuracy and efficiency through additional Cas9 mutations. The resulting extra-precise prime editor (xPE) achieved an edit-to-indel ratio of 354:1, representing a major improvement in precision. However, the xPE system still showed slightly lower editing efficiency, prompting the team to protect the prime editing RNA (pegRNA) from degradation using a La poly-U binding protein. This final refinement produced the very-precise prime editor (vPE), which achieved a 3.2-fold increase in editing efficiency and a striking 465:1 edit-to-indel ratio.
The researchers believe these advances could make prime editing significantly safer for therapeutic use. The new vPE system, they note, can be readily integrated into existing gene editing platforms, paving the way for more precise, reliable, and low-risk genome correction in future cell and gene therapies. As coauthor Robert Langer explained, the goal is to achieve the same balance sought in any medical treatment—high effectiveness with minimal side effects.
