DNA shape explains crucial gene-therapy challenges
Why it matters: Understanding DNA shape's role in CRISPR errors could lead to safer, more effective gene therapies.
- CRISPR-Cas9 is a powerful DNA-editing tool that has revolutionized genetic disease therapies and cancer treatment, but its imperfection leads to misplaced edits.
- Professor David Rueda (LMS and Imperial College London) highlights that CRISPR errors cost the industry an estimated $0.3 to $0.9 billion annually due to off-target profiling, guide redesigns, and delays.
- DNA topology, specifically negative supercoiling (where DNA is underwound and buckles into loops), is shown to be as critical as DNA sequence in affecting CRISPR accuracy, a finding supported by multiple labs including those at LMS and Sheffield.
- Quentin Smith's Ph.D. work involved designing new supercoiled DNA minicircles, which are tiny loops of DNA that mimic cellular torsional stress, enabling the team to capture CRISPR-DNA interactions in unprecedented detail.
New research published in Nature by scientists at MRC Laboratory of Medical Sciences (LMS), Imperial College London, and the University of Sheffield reveals that the physical twisting of DNA, known as supercoiling, significantly impacts the accuracy of CRISPR gene-editing, leading to costly off-target edits. By developing novel nanometer-sized DNA minicircles, the team observed unprecedented interactions between CRISPR and DNA, offering crucial insights to potentially eliminate these errors.
