UCI researchers develop breakthrough DNAzyme for precise gene silencing in disease treatment

Scientists at the University of California, Irvine, have made a significant breakthrough in gene silencing technology by developing a DNA enzyme, known as DNAzyme, that can selectively target and cut disease-associated RNA strands while leaving healthy strands untouched. This groundbreaking discovery has the potential to revolutionize the treatment of various conditions, including cancer, infectious diseases, and neurological disorders.

DNAzymes are a type of nucleic acid enzyme that can cleave other molecules. The research team at UCI successfully created the Dz 46 enzyme through chemical modifications, enabling it to specifically target and cut allele-specific RNA mutations in the KRAS gene. Mutations in this gene, responsible for regulating cell growth and division, are found in approximately 25% of all human cancers. The team’s approach to evolving this enzyme was detailed in a recent publication in the journal Nature Communications.

According to corresponding author John Chaput, a professor of pharmaceutical sciences at UCI, developing DNAzymes capable of functioning effectively within the natural conditions of cellular systems has posed significant challenges. However, the team’s results indicate that chemical evolution techniques could pave the way for the development of novel therapies across a wide range of diseases.

While gene silencing has been available for over two decades, existing FDA-approved drugs utilizing this technology cannot discriminate between single point mutations in RNA strands. The Dz 46 enzyme overcomes this limitation by precisely identifying and cutting specific gene mutations, offering patients a groundbreaking form of precision medicine.

Structurally, the DNAzyme resembles the Greek letter omega and functions as a catalyst by accelerating chemical reactions. The “arms” of the enzyme bind to the target region of the RNA, while the loop binds to magnesium, facilitating the folding and cleaving of RNA at a specific site. However, generating DNAzymes with robust multiple turnover activity under physiological conditions presented a challenge, as these enzymes typically rely on magnesium concentrations not typically found within human cells.

To address this issue, the team re-engineered the DNAzyme using chemical modifications to reduce its dependence on magnesium while maintaining high catalytic turnover activity. This achievement represents one of the first instances, if not the first, of successfully attaining such functionality. The researchers now aim to advance Dz 46 to a stage where it can undergo pre-clinical trials.

The study involved the participation of Kim Thien Nguyen, a project scientist, and Turnee N. Malik, a postdoctoral scholar, both from the Department of Pharmaceutical Sciences at UCI.

The researchers and UCI have filed provisional patent applications for the chemical composition and cleavage preference of Dz 46. John Chaput also serves as a consultant for drug development company 1E Therapeutics, which supported this research.

Source: University of California, Irvine

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