CRISPR Pioneer Feng Zhang and Team Expand RNA Editing Capabilities

CRISPR Gene editing

As gene editing becomes a core focus of research for numerous companies, researchers have developed a new technique to target RNA edits that had not previously been possible.

Feng Zhang, a pioneer of CRISPR technology at the Broad Institute of MIT, and his research team have developed a new CRISPR gene editing strategy called RESCUE (RNA Editing for Specific C to U Exchange). CRISPR refers to Clustered Regularly Interspaced Short Palindromic Repeats that occur in the genome of certain bacteria, from which the system was discovered. The new strategy uses the deactivated Cas13 enzyme to guide RESCUE to targeted cytosine bases on RNA transcripts, Zhang and his MIT team announced in a statement. They used a “novel, evolved, programmable enzyme” to then convert unwanted cytosine into uridine, which thereby directs a change in the RNA instructions.

In its announcement, MIT said RESCUE significantly expands the landscape that CRISPR tools can target to include modifiable positions in proteins, such as phosphorylation sites. Those kinds of sites act as “on/off” switches for protein activity and are notably found in signaling molecules and cancer-linked pathways. RESCUE builds on REPAIR, a technology developed by Zhang’s team that changes adenine bases into inosine in RNA. The REPAIR platform used CRISPR-Cas13 to direct the active domain of an RNA editor, ADAR2, to specific RNA transcripts. From there it could convert the nucleotide base adenine to inosine.

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“To treat the diversity of genetic changes that cause disease, we need an array of precise technologies to choose from. By developing this new enzyme and combining it with the programmability and precision of CRISPR, we were able to fill a critical gap in the toolbox,” Zhang said in a statement.

The RESCUE program can be guided to any RNA of choice, the researchers said in the announcement. As part of their research, which was published in the journal Science, the researchers took showed how they can target natural RNAs in human cells, as well as 24 clinically relevant mutations in synthetic RNAs. Additionally, the research team discovered how to reduce off-target editing, while minimally disrupting on-target editing. Expanded targeting by RESCUE means that sites regulating activity and function of many proteins through post-translational modifications, such as phosphorylation, glycosylation, and methylation, can now be more readily targeted for editing, the MIT team said in its announcement.

Unlike editing DNA, RNA editing is reversible. That means that the new RESCUE platform can be used as a temporary solution to edit RNA. As an example, Zhang’s team used RESCUE to target RNA encoding β-catenin, which led to a temporary increase in β-catenin activation and cell growth. If that change was made permanent, Zhang’s team said the cell could become predisposed to cell growth and potential development of cancer.

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