Nature Biotechnology: Streamlining RNA Editing to Treat Genetic Diseases

The findings were published Feb.
10 in the journal Nature Biotechnology
.

What's special about this technology is that it effectively uses RNA-editing enzymes that are naturally present in human cells
.
These enzymes are called RNA-acting adenosine deaminase (ADARs)

Researchers have been exploring ways to use ADARs for RNA editing to correct G-to-A mutations underlying genetic disorders such as cystic fibrosis, Rett syndrome and Hurler syndrome
.
One of the big advantages of RNA editing over DNA editing is that changes in RNA are only temporary because of the short lifespan of RNA

In order to use ADARs for targeted A-to-I (or, in essence, A-To-G) editing on RNA, a short accessory strand of RNA, called a guide RNA, is required to guide ADARs to their target, and make the required changes there
.

A big challenge with this approach, explained Prashant Mali, a professor of bioengineering at the UC San Diego Jacobs School of Engineering, is that traditional guide RNAs are not efficient when using native ADARs inside cells, so they require external ADARs Enter the cell to work
.
"But the problem is, that complicates delivery

To overcome these problems, Mali and his colleagues engineered a new guide RNA that is highly efficient at recruiting the cell's own ADARs to edit precise target RNA regions

"We can simply inject a small piece of RNA into the cell and repair the mutation in vivo
.
We don't need to provide any additional enzymes

The team designed guide RNAs to target a single G-to-A mutation in Hurler syndrome

One aspect that makes new guide RNAs effective is that they are longer than traditional guide RNAs
.
"This basically makes the ADARs that are already inside the cell more adherent and bind to them," Mali said

Other unique design features make it more stable and precise than traditional guide RNAs
.
They can last for days and stay longer in the region of target RNA, which is usually destroyed by cells quickly

The research is still in its early stages, Mali said, and "it remains to be seen how this RNA editing technology will work in primates
.
" The team's next steps will focus on improving the delivery of guide RNAs into cells
.

"I hope this work opens more doors for RNA editing as another gene therapy tool
.
"

Mali co-founded Shape Therapeutics, a Seattle-based biotech startup that is working to bring this and several other RNA-editing techniques developed in Mali's lab into the clinic
.

article title

Robust in vitro and in vivo RNA editing via recruitment of endogenous ADARs using circular guide RNAs