New RNA editing tool can eradicate genetic diseases

Scientists have created a new gene editing tool that tweaks the individual RNA 'letters' in human cells without making changes to the entire genome, paving the way for therapies that can reverse disease-causing mutations.
The molecular system, called RNA Editing for Programmable A to I Replacement (REPAIR) has profound potential as a tool for both research and disease treatment.
REPAIR is based on the gene editing tool CRISPR that can be used to modify DNA in cells.
The new system, developed by scientists from The Broad Institute and Massachusetts Institute of Technology (MIT) in the US, can change single RNA nucleosides in mammalian cells in a programmable and precise fashion.

REPAIR has the ability to reverse disease-causing mutations at the RNA level, as well as other potential therapeutic and basic science applications.
"The ability to correct disease-causing mutations is one of the primary goals of genome editing," said Feng Zhang, from MIT.

"So far, we've gotten very good at inactivating genes, but actually recovering lost protein function is much more challenging," said Zhang.
"This new ability to edit RNA opens up more potential opportunities to recover that function and treat many diseases, in almost any kind of cell," he said.
REPAIR has the ability to target individual RNA letters, or nucleosides, switching adenosines to inosines.

These letters are involved in single-base changes known to regularly cause disease in humans.
In human disease, a mutation from G to A is extremely common; these alterations have been implicated in, for example, cases of focal epilepsy, Duchenne muscular dystrophy, and Parkinson's disease.
REPAIR has the ability to reverse the impact of any pathogenic G-to-A mutation regardless of its surrounding nucleotide sequence, with the potential to operate in any cell type.
Unlike the permanent changes to the genome required for DNA editing, RNA editing offers a safer, more flexible way to make corrections in the cell.
"REPAIR can fix mutations without tampering with the genome, and because RNA naturally degrades, it's a potentially reversible fix," said David Cox, a graduate student in Zhang's lab.

To create REPAIR, the researchers systematically profiled the CRISPR-Cas13 enzyme family for potential "editor" candidates.
They selected an enzyme from Prevotella bacteria, called PspCas13b, which was the most effective at inactivating RNA.
The team engineered a deactivated variant of PspCas13b that still binds to specific stretches of RNA but lacks its "scissor-like" activity, and fused it to a protein called ADAR2, which changes the nucleoside adenosine to inosine in RNA transcripts.
"The success we had engineering this system is encouraging, and there are clear signs REPAIRv2 can be evolved even further for more robust activity while still maintaining specificity," said Omar Abudayyeh, also a graduate student in Zhang's lab.