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What’s the Best Way to Deliver Prime Editing?

Written by Charlotte Harrison, Science Writer 

Prime editing is a new type of genome editing technology. It essentially builds on CRISPR and could overcome some of CRISPR’s limitations, such as unwanted genetic changes. Yet to realise the full potential of prime editing as a medical tool, the technology needs to be delivered safely and effectively to the desired place in the body. 

A recent review by Elena Ivanova from Columbia University highlights the key requirements of a drug delivery system for prime editing, and evaluates the advantages and disadvantages of potential drug delivery vehicles. 

Prime editing versus CRISPR  

In CRISPR, the Cas9 enzyme cuts double-stranded DNA, and the cell’s DNA repair machinery adds, deletes, or changes the DNA. The fact that CRISPR relies on double-stranded breaks can cause problems; during the repair of these double-stranded breaks, unwanted insertions and/or deletions can occur, leading to unintended genetic alterations.   

Prime editing uses single-strand DNA breaks. Like CRISPR, prime editing requires a Cas endonuclease and a guide RNA. But prime editing uses an impaired form of Cas9 that nicks the DNA rather than making double-strand breaks. The enzyme is fused to a transcriptase that is linked to a guide RNA that identifies the target site. By avoiding the sporadic DNA repair associated with CRISPR, prime editing could improve the accuracy of gene editing. 

Key needs for delivering prime editing technologies 

Delivery systems for prime editing technologies is an emerging field. As yet, efficient in-vivo delivery has not yet been demonstrated. In her review, Ivanova notes that a non-viral delivery system is preferred for patient safety reasons. The review highlights the four main requirements of a drug delivery system:  

  • Most importantly, the delivery system must be able to deliver the entire prime editing complex – that is, the enzyme, reverse transcriptase and guide RNA.  
  • An optimal delivery system must fully cloak both the protein and RNA components from the bloodstream and tissue interactions until it has arrived at the target cell. 
  • The delivery system must enable intracellular and intranuclear (or intramitochondrial) uptake in the target cell.  
  • The delivery system should enable a path for regulatory approval and so cannot be extremely complex. 

The review then moves to the potential advantages and disadvantages of specific drug delivery systems, including liposomes, micelles, polymer-based systems, dendrimers and rigid nanoparticles. The author notes that the optimal delivery vehicle will likely change depending on the specific disease target.  

Based on the above four criteria, the author opines that liposomes are the most promising candidate for delivering prime editing. Liposomes are vesicles composed of a lipid bilayer that acts as a protective barrier between a therapeutic and the external surrounding fluid. They are not without their problems though. Future research will need to address issues of potential toxicity and instability in the circulatory system.

Image Credit: Canva

More on these topics

CRISPR / Gene Editing / Prime Editing