Grant: Project Grant

Thousands of human genetic diseases ranging from cystic fibrosis to muscular dystrophy 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. However, modern-day gene editing technology could revolutionize the treatment of these diseases by allowing researchers to permanently correct the underlying genetic mutations causing these diseases. For example, a recently described system called CRISPR/Cas9 can be used to precisely delete, insert, or edit genetic information (DNA) in cell and animal models. In the future, this system could also be applied to the treatment of many of the human diseases listed above by replacing the defective copy of a gene with a correct copy. However, there still remains several hurdles that must be overcome to translate this technology to the clinic. The greatest of these challenges 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 eventual human applications. My lab has recently uncovered a way to decrease off-target DNA cutting by CRISPR/Cas9 by over 10,000-fold. This project will broaden and extend our findings to enable precise cleavage of any gene using CRISPR/Cas9. In addition, we will apply our findings to not only Cas9 DNA cutting, but also to optimizing the precision of safer gene editing technology that has recently been invented. Ultimately, we hope to partner with a biotechnology company to advance the development of safer, next-generation gene editing technology for humans.