The most popular method of genetic editing, CRISPR, might not be the safest approach to treat incurable diseases, a new study has highlighted.

The study, published by the University of California San Diego and Yale University, suggests small nuclear RNA base editing could be a safer approach to treating diseases. The innovative approach found small nuclear RNA base editing worked better on complex RNAs, created fewer accidental edits in the genome and, in a model of cystic fibrosis, rescued faulty genes more effectively.

CRISPR, short for ‘clustered regularly interspaced short palindromic repeats’, is a method of genetic editing that uses RNA and bacterial proteins to edit DNA. It was adapted from a method used by bacteria as an immune defence against the DNA of viruses. 

When the method is used by scientists to edit human DNA, however, there can be unintended consequences. These can include accidental edits that can cause life-threatening health conditions in the near term. The long-term effects of CRISPR editing are unknown and may include an increased risk of cancer. 

It is also possible that, with the CRISPR approach, the immune responses kills edited cells, undoing any good done by CRISPR and potentially causing more severe health issues, according to Gene Yeo, corresponding author on the study.  

Yeo and a team of researchers tested two types of editing systems that, like CRISPR, use RNA to make revisions to genetic code. Unlike CRISPR, however, the systems make more specific, temporary modifications. 

Clear advantages to the small nuclear RNA approach 

“Human-based editing systems,” as opposed to bacteria-based editing systems, “have less potential for issues,” Yeo said. 

Both editing systems used small nuclear RNAs — RNA molecules that don’t make proteins, located inside the nucleus of cells — to swap out certain “letters” in the genetic code. RNA letters are A, U, C and G (adenine, uracil, cystosine and guanine). They were able to change A so that it was read as G and U so that it was read as Ψ. 

When compared to the best current RNA editing tools, the small nuclear RNA approach showed clear advantages. 

“The addition of a nuclear localisation sequence was instrumental to the early success of CRISPR-Cas9,” said Aaron Smargon, first author and an assistant project scientist in Yeo’s lab. “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. 

Rewriting the genetic code in a minimally invasive manner could lead to safer, more precise treatments for a variety of diseases, including neurodegenerative, cardiovascular and immune. The demonstrated advantages of small nuclear RNA editing will pave the way for new applications that push the boundaries of medicine, Yeo suggests. 

“We are excited about continuing to advance the field of engineered RNA modifiers,” she added. 

 Bruno Quinney, Content Team, DDW