Point mutation, illustration
Computer graphic illustration depicting a point mutation. A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a sequence of DNA or RNA. Point mutations have a variety of effects on the downstream protein product consequences that are moderately predictable based upon the specifics of the mutation. These consequences can range from benign (e.g. synonymous mutations) to catastrophic (e.g. frameshift mutations), with regard to protein production, composition, and function.

Researchers at the University of California, San Diego (UCSD), and Seattle biotech Shape Therapeutics have engineered a special guide RNA that is designed to make RNA editing for the treatment of diseases easier.

The technology designed in this research makes use of RNA editing enzymes occurring naturally in the body’s cells called adenosine deaminases acting on RNA (ADARs), without requiring the addition of external ADARs.

In a proof-of-concept study published in Nature Biotechnology, the team showed that their approach was able to significantly reduce symptoms in a mouse model of Hurler syndrome, a rare genetic disease that causes build-up of big sugar molecules called glycosaminoglycans in the body.

RNA editing is currently being explored by a number of researchers as a method of treating genetic disease that is reversible, as RNA has a relatively short half-life. This could have benefits over editing DNA if unexpected off-target effects occur.

Previous attempts to do RNA editing using ADARs were problematic, as the guide RNAs needed to edit the genetic defect correctly were not good at using ADARs already present in the body. This meant external ADARs were needed along with the guide RNAs, which increases the risk of off-target effects and other problems.

In this study, Prashant Mali, PhD, a bioengineering professor at the UCSD Jacobs School of Engineering, and colleagues engineered a new guide RNA that can effectively use the ADARs found in the cell to edit genetic defects in the RNA.

“We can simply deliver just a small piece of RNA inside the cell and repair mutations in vivo. We don’t have to provide any extra enzymes,” said Mali in a press statement.

To test their technology, Mali and team used it to correct the genetic defect, a single G-to-A mutation, in Hurler syndrome in a mouse model. After two weeks, the treatment had corrected 7–17% of the defective RNAs in these mice. There was also a 33% decrease in build-up of the sugars that cause the symptoms of Hurler syndrome.

The new guide RNAs are longer than previous models and therefore more attractive for the ADARs in the cell to stick to. They are also more stable and precise than earlier guide RNAs and last for longer in the body due to their circular shape.

This research is at an early stage and needs to be tested in more animal models before it can move towards clinical trials. “I’m hopeful that this work opens the door even more for RNA editing as another gene therapy tool,” said Mali.

Mali is a co-founder of Shape Therapeutics, a Seattle-based biotech founded in 2018 that is developing the current research and other similar RNA editing technologies in the hope of bringing new therapeutics to the clinic.

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