New research led by Yale Cancer Center shows the creation of a next-generation CRISPR-Cas9 “off-switch” and precision tool to aid safe gene editing therapeutics in patients. Study scientists report the discovery improved gene editing accuracy and control across multiple disease-relevant genes including those implicated in human immunodeficiency virus (HIV) infection, Fanconi anemia, sickle cell disease, beta thalassemia, and others. The study was published today in the journal Nucleic Acids Research.
“While past approaches have used proteins or small molecules to inhibit CRISPR-Cas9, we designed chemically synthesized peptide nucleic acids that can precisely and tightly bind the targeting guide-RNA element within the Cas9 enzyme,” said Nicholas Economos, lead author of the study and an MD/PhD candidate in Genetics at Yale. “This allows us to impart very specific effects on Cas9 at low treatment doses to improve control and safety.”
Economos and scientists in the laboratory of Peter Glazer, MD, PhD, Robert E. Hunter Professor of Therapeutic Radiology, Professor of Genetics and Chair of the Department of Therapeutic Radiology at Yale Cancer Center, started this research as CRISPR-Cas9 technologies have developed rapidly in the past 10 years. However, tools to control the timing, duration, dose, safety, and accuracy of CRISPR-Cas9 technologies have lagged behind their implementation. The researchers note these complementary technologies are especially important to reduce potentially dangerous off-target editing (editing the wrong DNA sequence) made by Cas9, which limits the safety and implementation of Cas9 therapeutics, especially as next-generation Cas9 therapeutics aim to be delivered systemically throughout the human body to cure disease.
“CRISPR-modulating tools can improve safety and control of powerful Cas9 technologies across applications and for optimized next-generation human therapies,” added Glazer, who is senior author on the paper. “We hope to eventually move this useful tool toward the clinic to ensure safe gene editing therapeutics in patients.” Other Yale authors include: Elias Quijano, Kelly Carufe, and Dinithi Perera, PhD. Funding for this study was provided by grants from the National Institutes of Health (NIH).