New research could make it much simpler to repair disease-causing mutations in RNA without compromising precision or efficiency. The new RNA editing technology holds promise as a gene therapy for treating genetic diseases. In a proof of concept, researchers showed that the technology can treat a mouse model of Hurler syndrome, a rare genetic disease, by correcting its disease-causing mutation in RNA.
The new RNA editing technology holds promise as a gene therapy for treating genetic diseases. In a proof of concept, UC San Diego researchers showed that the technology can treat a mouse model of Hurler syndrome, a rare genetic disease, by correcting its disease-causing mutation in RNA. The findings are published Feb. 10 in Nature Biotechnology.
What’s special about the technology is that it makes efficient use of RNA editing enzymes that naturally occur in the body’s cells. These enzymes are called adenosine deaminases acting on RNA (ADARs). They bind to RNA and convert some of the adenosine (A) bases to inosine (I), which is read by the cell’s translation machinery as guanosine (G).
Researchers have been exploring RNA editing approaches with ADARs to correct the G-to-A mutation behind genetic disorders such as cystic fibrosis, Rett syndrome and Hurler syndrome. A big advantage of RNA editing — over DNA editing, for example — is that changes to RNA are only temporary, since RNA has a short lifespan. So even if off-target edits occur, they wouldn’t be there to stay.
To make a targeted A-to-I (or essentially, an A-to-G) edit on RNA using ADARs, a short accessory strand of RNA — called a guide RNA — is needed to guide ADARs to the target and make the desired change there.
A big challenge with this approach is that traditional guide RNAs are not efficient at using native ADARs in the cell, so they require external ADARs to be brought into the cell to work, explained Prashant Mali, a bioengineering professor at the UC San Diego Jacobs School of Engineering. «But the problem with that,» he added, «is that it makes delivery complicated. And it can result in more off targets.»
To overcome these issues, Mali and colleagues engineered a new kind of guide RNA — one that is extremely effective at recruiting the cell’s own ADARs to make edits at a precise target RNA region.
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Materials provided by University of California — San Diego. Original written by Liezel Labios. Note: Content may be edited for style and length.