Safer Base Editing Approach Developed

Gene editing is often explored for treating diseases that currently lack cures, but the widely used CRISPR technique raises safety issues. A team from the University of California San Diego and Yale University reports an alternative method based on base editing that could address many of these concerns.

While effective, CRISPR can trigger unintended consequences that may cause severe conditions and possibly heighten cancer risk. It can also provoke immune responses that destroy edited cells, negating benefits and potentially worsening health. Gene Yeo, senior author on the study published in Nature Chemical Biology, emphasizes that these risks underline the need for safer solutions.

Yeo and colleagues tested two approaches that rely on small nuclear RNAs (snRNAs), molecules found inside the cell nucleus. Unlike CRISPR’s bacterial-based design, these human-derived systems made precise, temporary modifications. The process allowed researchers to alter adenine (A) so that it was read as guanine (G) and to change uracil (U) so that it was read as Ψ.

Compared with existing RNA tools, the snRNA-based editors proved advantageous in several respects. They operated effectively on complex RNAs with multiple regions or those not normally translated into proteins. They produced far fewer unintended edits, making them potentially safer. In addition, in a cystic fibrosis model, the technique repaired faulty genes with greater efficiency.

The team’s thinking built on lessons from CRISPR technology. Aaron Smargon, first author of the study, explained, “The addition of a nuclear localization sequence was instrumental to the early success of CRISPR-Cas9. We wondered similarly whether spatial confinement of engineered RNA base editors to the nucleus—where all known RNA-guided base editing occurs in cells—would be beneficial.” 

Because this method can rewrite genetic code in a more targeted and controlled manner, it may open new therapeutic possibilities for conditions affecting the nervous, cardiovascular and immune systems. “We are excited about continuing to advance the field of engineered RNA modifiers,” Yeo said.