New Gene-Editing Tool Offers More Precision and Flexibility

Researchers at the University of Sydney have created a gene-editing instrument that is more precise and adaptable than the industry standard CRISPR, which has transformed genetic engineering in biotechnology, agriculture, and medicine.

To streamline editing and lower error rates, SeekRNA uses a programmable ribonucleic acid (RNA) strand that can locate insertion sites in genetic sequences directly.

A group at the School of Life and Environmental Sciences, led by Dr. Sandro Ataide, is creating the new gene-editing instrument. The study was published in Nature Communications.

We are tremendously excited by the potential for this technology. SeekRNA’s ability to target selection with precision and flexibility sets the stage for a new era of genetic engineering, surpassing the limitations of current technologies.”

Dr. Sandro Ataide, School of Life and Environmental Sciences, University of Sydney

Dr. Ataide said, “With CRISPR you need extra components to have a ‘cut-and-paste tool’, whereas the promise of seekRNA is that it is a stand-alone ‘cut-and-paste tool’ with higher accuracy that can deliver a wide range of DNA sequences.”

The double-helix genetic code of life is the target of CRISPR, which depends on breaking it into two strands. To insert the new DNA sequence, additional proteins or DNA repair machinery are required, which may result in errors.

Dr. Ataide added, “SeekRNA can precisely cleave the target site and insert the new DNA sequence without the use of any other proteins. This allows for a much cleaner editing tool with higher accuracy and fewer errors.”

Since the creation of CRISPR more than ten years ago, gene editing has allowed for the exploration of entirely new fields of study and application. It has improved fruit and crop disease resistance, lowered the cost and speed of human disease detection, aided in the hunt for a sickle cell disease cure, and made it possible to develop the ground-breaking cancer treatment known as (CAR) T-cell therapy.

We are very much in the early days of what gene editing can do. We hope that by developing this new approach to gene editing, we can contribute to advances in health, agriculture, and biotechnology.”

Ruth Hall, Joint Author and Professor, University of Sydney

Precise Genetic Targeting

SeekRNA originates from the IS1111 and IS110 family of naturally occurring insertion sequences found in bacteria and archaea (nucleus-free cells). These families of insertion sequence proteins have high target specificity, while the majority of them show little to no target selectivity.

SeekRNA has used this accuracy to produce its encouraging results thus far.

SeekRNA can be altered to fit any genomic sequence and insert the new DNA in an exact orientation using the accuracy of this insertion sequence family.

In the laboratory, we have successfully tested seekRNA in bacteria. Our next steps will be to investigate if the technology can be adapted for the more complex eukaryotic cells found in humans,” said Dr. Ataide.

The system described in this work has the benefit of efficiently moving genetic cargo with just one modestly sized protein and one short seekRNA strand. A 350 amino acid small protein and an RNA strand with 70–100 nucleotides make up seekRNA.

A system of this size could be enclosed in lipid nanoparticles or vesicles, which are biological nanoscale delivery vehicles, for delivery to target cells.

Direct Insertion to DNA

Another point of differentiation is this technology's ability to autonomously insert DNA sequences in the desired location, which is not achievable with many of the editing tools available today.

Current CRISPR technology has limitations on the size of genetic sequences that can be introduced. This restricts the scope of application.”

Rezwan Siddiquee, Research Associate and Study Lead Author, University of Sydney

Other teams worldwide are conducting similar investigations into the gene-editing potential of the IS1111 and IS110 families. Dr. Ataide notes that they rely on a much larger RNA version and have only demonstrated results for one member of the IS110 family. By using the shorter seekRNA itself and direct laboratory sampling, the Sydney team is improving its methodology.

Source:
Journal reference:

Siddiquee, R., et al. (2024) A programmable seekRNA guides target selection by IS1111 and IS110 type insertion sequences. Nature Communications. doi.org/10.1038/s41467-024-49474-9

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