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UCI Researchers Develop Highly Targeted DNA Enzyme for Gene Silencing at the Single-Molecule Level

Researchers at the University of California, Irvine (UCI) have made a significant breakthrough by developing a DNA enzyme, or DNAzyme, that can differentiate between two RNA strands within a cell. This groundbreaking technology enables the DNAzyme to selectively target and cut disease-associated RNA strands while leaving healthy strands intact. The potential applications of this "gene silencing" technology are vast, with implications for treating cancer, infectious diseases, and neurological disorders.

The UCI team focused on the KRAS gene, which is a master regulator of cell growth and division and is found in 25 percent of human cancers. They engineered the Dz 46 enzyme using chemical methods to specifically target the allele-specific RNA mutation in the KRAS gene. Their success in evolving this enzyme was recently published in the journal Nature Communications.

According to corresponding author John Chaput, a professor of pharmaceutical sciences at UCI, generating DNAzymes that can effectively function within the natural conditions of cell systems has been a challenging task. However, the team's findings suggest that chemical evolution techniques could pave the way for the development of novel therapies across a wide range of diseases.

While gene silencing techniques have been available for more than two decades, existing technologies cannot distinguish and target a single point mutation in an RNA strand. The Dz 46 enzyme, on the other hand, has the ability to precisely identify and cut a specific gene mutation. This level of precision opens up new possibilities for innovative and personalized treatment approaches.

The structure of the DNAzyme resembles the Greek letter omega and acts as a catalyst by accelerating chemical reactions. The DNAzyme's "arms" bind to the target region of the RNA, while the loop binds to magnesium, enabling the enzyme to fold and cut the RNA at a specific site. Overcoming the challenge of developing DNAzymes with robust activity under physiological conditions required ingenuity, as DNAzymes typically rely on concentrations of magnesium that are not naturally found within human cells.

To address this issue, the researchers re-engineered the DNAzyme using chemical modifications that reduced its dependency on magnesium while maintaining high catalytic turnover activity. This achievement represents one of the earliest examples of this approach. The next step for the research team is to further advance Dz 46 and prepare it for pre-clinical trials.

In addition to John Chaput, other members of the UCI research team, such as Kim Thien Nguyen and Turnee N. Malik from the Department of Pharmaceutical Sciences, contributed to this study. The researchers and UCI have filed provisional patent applications related to the chemical composition and cleavage preference of Dz 46. Furthermore, John Chaput serves as a consultant for 1E Therapeutics, a drug development company that supported this research.

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