Researchers from the University of California, Irvine have developed a new gene silencing technology that could revolutionize the treatment of cancer, infectious diseases, and neurological disorders. The team has successfully created a DNA enzyme, or DNAzyme, that can differentiate between two RNA strands inside a cell and cut the disease-associated strand while leaving the healthy strand untouched.
Gene silencing, a technology available for over 20 years, has been incorporated in some FDA-approved drugs. However, none of these can differentiate a single point mutation in an RNA strand. The DNAzyme developed by UCI's team, called Dz 46, can identify and cut a specific gene mutation, offering patients an innovative, precision medicine treatment.
DNAzymes are nucleic acid enzymes that cut other molecules. UCI's team developed Dz 46, which targets the allele-specific RNA mutation in the KRAS gene, a master regulator of cell growth and division, found in 25 percent of all human cancers. The team's method of enzyme evolution has been recently published in the online journal Nature Communications.
"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 the development of novel therapies for a wide range of diseases."
The DNAzyme takes the shape of the Greek letter omega and acts as a catalyst by accelerating chemical reactions. 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 specific site. However, generating DNAzymes with robust multiple turnover activity under physiological conditions required ingenuity since DNAzymes are highly dependent on concentrations of magnesium not found inside a human cell.
"We solved that problem by re-engineering the DNAzyme using chemistry to reduce its dependency on magnesium and did so in such a way that we could maintain high catalytic turnover activity," Chaput said. "Ours is one of the very first, if not the first, example of achieving that. The next steps are to advance Dz 46 to a point that it's ready for pre-clinical trials."
UCI and the researchers have filed provisional patent applications on the chemical composition and cleavage preference of Dz 46. Chaput is a consultant for drug development company 1E Therapeutics, which supported this work.
The successful development of this technology could pave the way for new treatments for various diseases by allowing doctors to target specific gene mutations. While there is still a long way to go before it becomes a viable treatment option, the development of Dz 46 is a promising breakthrough.
Could this help to fight HD?
While the newly developed DNAzyme technology is still in its early stages of development and has not yet been tested for its efficacy in treating Huntington's Disease (HD), it does hold potential as a tool for fighting this debilitating condition.
Huntington's Disease is a neurodegenerative disorder caused by a mutation in the huntingtin gene, which leads to the production of a toxic protein that damages nerve cells in the brain. The gene silencing technology that the UCI researchers have developed has the potential to specifically target and cut the disease-associated RNA strand, leaving the healthy strand intact. This precision approach could potentially reduce the production of the toxic protein associated with HD, slowing down the progression of the disease.
However, it is important to note that HD is a complex condition and targeting a single gene mutation may not be sufficient to completely halt or reverse the damage caused by the disease. Additionally, the DNAzyme technology is still in the early stages of development, and further research and testing will be required to determine its effectiveness and safety as a treatment for HD. Nonetheless, the development of this technology is a promising step forward in the fight against neurodegenerative disorders like HD.