Grant: Project Grant

Thousands of human genetic diseases ranging from cystic fibrosis to sickle cell anemia are caused by a mutation in a single known gene. Yet, despite extensive effort, we have been unable to identify conventional pharmaceuticals to treat many of them. Recently developed gene editing technologies are poised to change this. These tools afford researchers and clinicians the possibility of permanently correcting the underlying genetic mutations that cause these diseases. One example of such a system is CRISPR/Cas9, which can be used to delete, insert, or edit genetic information (DNA) in a precise manner. It is currently being tested in >50 early-stage clinical trials aimed at replacing or repairing defective copies of genes in various human organs and tissues. However, one of the primary concerns of this technology is imperfect specificity. While these tools alter the sequence at the correct target location the majority of the time, they also occasionally alter the genetic information at off-target locations. Unintended DNA cleavage or editing could have detrimental consequences in humans and could give rise to diseases such as cancer. This project proposes to dramatically improve the precision of CRISPR/Cas9, making it safer for human applications. My lab has recently uncovered a new way to dramatically decrease off-target DNA cutting by CRISPR/Cas9. This project will extend and broaden our findings to enable precise cleavage of any gene using CRISPR/Cas9, while simultaneously gaining molecular insight into how this occurs. In addition, we will apply our findings to optimize the precision of newer, and potentially safer, gene editing technologies that have recently been invented.