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A*STAR researchers have developed a technique that can correct disease-causing single-letter mutations in our genetic code.

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Correcting glitches in human genes

31 Aug 2021

Precise and efficient C:G to G:C gene-editing enzymes could pave the way for new treatments for genetic diseases.

Every minute, millions of text messages are sent and received worldwide, with these quick exchanges often containing a typo or two. However, when it comes to our DNA sequences, even a single ‘typo’ can have disastrous consequences.

These single-letter changes, known as single nucleotide polymorphisms (SNPs), are the most prevalent mutations in humans. While most SNPs are harmless, others have serious consequences in relation to genetic diseases. For example, when the C nucleotide takes the place of a G in specific genes, the person develops cystic fibrosis, a condition affecting the respiratory and digestive systems. In adults, the accumulation of such spontaneous mutations can also lead to severe diseases such as cancer. Thousands of such genetic diseases exist.

Gene-editing technologies such as CRISPR have the potential to correct these genetic mistakes. However, gene editors are not quite ready for broad clinical applications yet— current iterations are unable to make precise changes effectively.

To overcome these limitations, a team of researchers from A*STAR’s Genome Institute of Singapore (GIS) set out to develop next-generation gene editors, capable of making more targeted and precise amendments to the human genome.

The team, led by Wei Leong Chew, a Senior Research Scientist and Associate Director at GIS, screened over 30 C-to-G base editor (CGBE) candidates to mine for the most effective molecular machinery for correcting C to G mutations. The researchers developed a technology that operates via a three-step mode of action: First, a guide RNA leads the Cas9 enzyme to a chosen gene in a sequence. Next, another enzyme known as deaminase cuts out the defective C from the sequence. Finally, a repair protein fills the gap in the DNA, installing a G in the C’s former spot.

Next, they validated these leads, optimized the technology, and targeted genes linked to genetic conditions including dyslipidemia, hypertrophic cardiomyopathy and deafness. The team found that selected CGBEs could interrogate disease-associated genes, efficiently identifying and modifying disease-associated mutations while minimizing the risk of unintended off-target.

“In addition to this new chemistry, they exhibit several key features and advantages. These include a lower rate of byproducts (insertions, deletions, substitutions) as compared to editing with CRISPR-Cas9 only, which minimizes unintended disruption to gene function,” explained Chew.

This unprecedented accuracy opens new treatment possibilities that target approximately 40 percent of SNPs associated with serious genetic disorders. Given this tremendous potential to help patients, the team is conducting follow-up studies to test its safety. “We are working to ensure our CGBE and CRISPR-Cas modalities are both effective and safe in disease models before their envisioned development towards the clinic,” Chew said. Building on their breakthrough, the team also has its sights set on creating more genome editors by utilizing the insights gained from this work.

The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore (GIS).

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References

Chen, L., Park J.E., Paa, P., Rajakumar, P. et al. Programmable C:G to G:C genome editing with CRISPR-Cas9-directed base excision repair proteins. Nature Communications 12, 1384 (2021) | article

About the Researcher

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Wei Leong Chew

Senior Research Scientist

Genome Institute of Singapore
Wei Leong Chew is a Senior Research Scientist at the Genome Institute of Singapore (GIS). His team develops technologies that make pinpoint changes to genes. His work provided the first demonstrations of multi-organ gene editing, disease gene correction with CRISPR-Cas9, and insights into the safety profile of these new nucleic acid therapeutics. He holds >10 patents and technology disclosures in the areas of gene editing, gene therapy, and nucleic acid technologies. Chew Wei Leong is the recipient of the President’s Science and Technology Awards – Young Scientist Award 2020.

This article was made for A*STAR Research by Wildtype Media Group