Small Nuclear RNA Base Editing a Safer Alternative to CRISPR, UC San Diego Researchers Find

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• Erin Prater- [email protected]

Media contact:

• Lizelda Lopez- [email protected]

Topics covered:

• CRISPR
• Genetic editing
• Small nuclear RNA editing
• Engineered RNA modifiers
• Cystic fibrosis.

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Genetic editing holds promise to treat incurable diseases, but the most popular method - CRISPR - sometimes does more harm than good. A new study from University of California San Diego and Yale University researchers highlights an innovative alternative approach that may be safer.

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 defense 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. What's more, the long-term effects of CRISPR editing are unknown and may include an increased risk of cancer.

Another possible unwanted outcome: an immune response that kills edited cells, undoing any good done by CRISPR and potentially causing more severe health issues, according to Gene Yeo, PhD, corresponding author on the study. Yeo is a professor in the Department of Cellular and Molecular Medicine at UC San Diego School of Medicine and director of the Sanford Stem Cell Innovation Center and the Center for RNA Technologies and Therapeutics at the Sanford Stem Cell Institute.

On a quest for safer options, Yeo and team 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.

"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:

• It worked better on complex RNAs, including those with many sections and those that don't normally code for proteins.
• It proved safer, creating far fewer accidental edits in the genome.
• And in a model of cystic fibrosis, the method rescued faulty genes more effectively.

The idea for the study originated from a key technological insight from CRISPR.

"The addition of a nuclear localization sequence was instrumental to the early success of CRISPR-Cas9," said Aaron Smargon, Ph.D., 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 and team predict.

"We are excited about continuing to advance the field of engineered RNA modifiers," Yeo said.

The study was published in Nature Chemical Biology on Sept. 18, 2025.

Link to full study.

Additional co-authors on the study include: Deepak Pant, Trent A. Gomberg, Sofia Glynne, Jonathan Nguyen and Jack T. Naritomi at UC San Diego; and Christian Fagre and Wendy V. Gilbert at Yale University.

The study was funded, in part, by the National Institutes of Health (grants #S10 OD026929, R01HG004659, U24 HG009889 and R01GM101316), the National Science Foundation (grant 2330451) and the Hartwell Foundation.

Yeo and Smargon have filed for a patent related to this work. Yeo is a cofounder and member of the board of directors, scientific advisory board member, equity holder and paid consultant for Eclipse BioInnovations. Yeo's interests have been reviewed and approved by UC San Diego in accordance with its conflict-of-interest policies. Gilbert is a co-founder and scientific advisory board member for Cloverleaf Bio. Gilbert's interests have been reviewed and approved by Yale University in accordance with its conflict-of-interest policies. The authors declare no other competing interests.