New Split Gene-Editing Tool Promises to Reduce Unwanted Mutations That Cause Disease by Over 70%

A group of engineers at Rice University has devised a novel approach to enhance the precision and control of a gene-editing tool.

This innovative method involves splitting the tool into two components, which only reassemble in the presence of a specific small molecule. According to the team, their novel tool could correct around half of the mutations that cause disease.

Split Gene Editor

Led by chemical and biomolecular engineer Xue Sherry Gao, the research team developed a CRISPR-based gene editor targeting adenine, a fundamental component of DNA.

This split editor remains inactive until the binding molecule is introduced, at which point it becomes operational. In contrast to the unaltered original, the split version demonstrates increased precision and a narrower operational window, reducing the likelihood of unintended alterations, according to the team.

Notably, the small molecule used to trigger the reassembly is already in use as an anti-cancer and immunosuppressive drug. The study highlights the split editor's successful performance in human cell cultures and live mice.

The team reports that the method accurately edited a single base pair on a target gene, which holds significant therapeutic potential given the role of single base-pair mutations in numerous diseases.

Potentials of the Split Editing Tool

Lead author Hongzhi Zeng emphasized the substantial impact of this tool, saying: "This tool has the potential to correct nearly half of the disease-causing point mutations in our genome."

However, Zeng further noted that existing adenine base editors are consistently active, raising the risk of unintended genome modifications alongside the desired corrections.

The research team addressed this concern by implementing an "on/off" switch. They divided the adenine base editor into two separate proteins, which remain inactive until sirolimus, also known as rapamycin, is introduced.

This molecule, discovered in 1972 in soil bacteria on Easter Island, is already FDA-approved for use in cancer therapies and other medical procedures.

Zeng explained the mechanism, saying: "Upon introduction of this small molecule, the two separate inactive fragments of the adenine base editor are glued together and rendered active.

As the body metabolizes the rapamycin, the two fragments disjoin, deactivating the system." Aside from the enhanced precision and control, this split approach offers additional benefits.

"Compared to an intact editor, our version reduces overall off-target edits by over 70% and increases the accuracy of on-target edits," Zeng noted.

In partnership with Zheng Sun from Baylor College of Medicine, the team focused on the PCSK9 gene, which plays a crucial role in controlling blood cholesterol levels.

Gao, the Ted N. Law Assistant Professor of Chemical and Biomolecular Engineering, anticipated wider uses for this divided genome-editing tool in tackling pivotal questions in human health with increased accuracy and safety measures.

The findings of the research team were published in the journal Nature Communications.