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CRISPR pioneer Zhang targets brain diseases with new RNA-editing system

The CRISPR enzyme Cas13 (pink), part of the RESCUE platform, uses a special guide (red) to target RNAs (blue) in the cell. (Stephen Dixon)

Feng Zhang, a gene-editing pioneer at the Broad Institute of MIT and Harvard, has garnered headlines lately for starting up Beam Therapeutics and raising $222 million to fund its research. Now, Zhang is rolling out his latest invention—a new strategy for editing RNA that his team says could someday be used to treat brain diseases like Alzheimer’s.

Zhang and colleagues developed a new system they call RNA Editing for Specific C to U Exchange (RESCUE). In cells, they used the technology to convert the gene variant APOE4—a risk factor for late-onset Alzheimer’s disease—into the non-pathogenic variant APOE2. They described the research in the journal Science.

CRISPR editing of DNA uses the enzyme Cas9 to snip DNA at specific locations. Targeting RNA instead can offer some advantages, because it avoids altering DNA permanently. Zhang’s team used a deactivated form of a different enzyme, Cas13, to target RNA.

RESCUE targets one of the four main “bases” of RNA, cytosine. Using a programmable enzyme, Zhang’s team converted pathogenic cytosine into uridine, which in turn changed the instructions RNA provided for, say, protein synthesis.

The researchers showed they could use RESCUE to target natural RNAs in cells, as well as “24 clinically relevant mutations in synthetic RNAs,” they said in a statement. They fine-tuned the technology to avoid off-target editing, a major concern that has slowed down the development of CRISPR for use in people.

Zhang’s team wanted to test RESCUE in Alzheimer’s because there are only two differences between the amino acid sequence for the risk variant APOE4 and that of the non-pathogenic APOE2. The used the technology to convert APOE4’s cytosines into an APOE2 sequence, effectively erasing the Alzheimer’s risk, they reported.

Another advantage of RNA editing is that it can be reversed. The MIT researchers showed in their study that they could use RESCUE to temporarily ramp up the activation of the protein beta-catenin, which could be useful in wound healing.

RESCUE builds on another system developed at the Broad called RNA Editing for Programmable A to I Replacement (REPAIR), which Zhang’s team reported in 2017. That technology changes the nucleoside adenosine (A) to inosine (I), which the researchers said could prove useful in treating diseases like Duchenne muscular dystrophy and Parkinson’s.

Several other research groups are working on RNA-editing technologies, including a team at the University of California, San Diego (UCSD), which used an RNA-targeted Cas9 system in lab models of myotonic dystrophy two years ago. A UCSD spinoff that’s developing the technology, Locana, raised $55 million in May of this year and is now working on tackling diseases like Huntington’s and amyotrophic lateral sclerosis.

The Broad’s Zhang says more work will have to be done before RESCUE can be tested in people. Meanwhile, he’s making the tool publicly available through the repository Addgene, so other researchers can use it to study disease-related mutations.

“To treat the diversity of genetic changes that cause disease, we need an array of precise technologies to choose from,” Zhang said in the statement. “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.”