Key Points
- Researchers from the University of California, Irvine have developed a DNA enzyme that can distinguish between two RNA strands inside a cell and cut the disease-associated strand while leaving the healthy strand intact.
- This breakthrough “gene silencing” technology could revolutionize the development of DNAzymes for treating cancer, infectious diseases and neurological disorders.
- The Dz 46 enzyme specifically targets the allele-specific RNA mutation in the KRAS gene found in 25 percent of all human cancers, offering patients an innovative, precision medicine treatment.
Scientists at the University of California, Irvine have developed a groundbreaking DNA enzyme, called Dz 46, that can identify and cut a specific gene mutation in a cell. This technology, known as “gene silencing,” could be used to develop DNAzymes to treat a variety of diseases including cancer, infectious diseases, and neurological disorders. Their findings were recently published in the online journal Nature Communications.
The Dz 46 enzyme targets the allele-specific RNA mutation in the KRAS gene, which is the master regulator of cell growth and division, found in 25 percent of all human cancers. The team used chemistry to develop the enzyme, which can distinguish between two RNA strands and cut the disease-associated strand while leaving the healthy strand intact.
“Generating DNAzymes that can effectively function in the natural conditions of cell systems has been more challenging than expected,” said corresponding author John Chaput, UCI professor of pharmaceutical sciences. “Our results suggest that chemical evolution could pave the way for development of novel therapies for a wide range of diseases.”
Gene silencing has been available for more than 20 years, but none can distinguish a single point mutation in an RNA strand. The Dz 46 enzyme is revolutionary because it can identify and cut a specific gene mutation, offering patients an innovative, precision medicine treatment.
The DNAzyme, which looks like the Greek letter omega, accelerates chemical reactions by acting as a catalyst. The “arms” on the left and right bind to the target region of the RNA, and the loop binds to magnesium and folds and cuts the RNA at a very specific site.
DNAzymes are normally dependent on concentrations of magnesium not found inside a human cell. To solve this problem, the team re-engineered the Dz 46 enzyme using chemistry to reduce its dependency on magnesium, maintaining high catalytic turnover activity. The team has filed provisional patent applications on the chemical composition and cleavage preference of Dz 46.
Kim Thien Nguyen, project scientist, and Turnee N. Malik, postdoctoral scholar, both from the Department of Pharmaceutical Sciences, also participated in this study. Chaput is a consultant for drug development company 1E Therapeutics, which supported this work.
The next steps for the team are to advance Dz 46 to a point that it’s ready for pre-clinical trials. The development of this innovative technology could lead to the development of DNAzymes for treating a wide range of diseases, and offer a new level of precision medicine for patients.
