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Feng Zhang, a pioneer of gene editing at the Broad Institute of MIT and Harvard, recently made headlines for launching Beam Therapeutics and raised $ 222 million to fund his research. Now, Zhang unveils her latest invention – a new RNA editing strategy that, according to her team, could one day be used to treat brain diseases like Alzheimer's.
Zhang and his colleagues have developed a new system that they call RNA Editing for a specific exchange C (U) (RESCUE). In the cells, they used the technology to convert the APOE4 gene variant – a risk factor for late-onset Alzheimer's disease – as a non-pathogenic APOE2 variant. They described the research in the journal Science.
The CRISPR edition of DNA uses the enzyme Cas9 to cut DNA at specific locations. Instead, targeting RNA may have some benefits because it avoids permanently altering the DNA. Zhang's team used a deactivated form of another enzyme, Cas13, to target RNA.
RESCUE targets one of the four main "bases" of RNA, cytosine. Using a programmable enzyme, Zhang's team converted the pathogenic cytosine to uridine, which in turn modified the RNA instructions for protein synthesis, for example.
The researchers showed that 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 tweaked the technology to avoid out-of-target changes, a major concern that slowed the development of CRISPR for use in humans.
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Zhang's team wanted to test RESCUE in Alzheimer's because there were only two differences between the amino acid sequence of the APOE4 risk variant and that of non-pathogenic APOE2. They used the technology to convert APOE4 cytosines into an APOE2 sequence, effectively wiping out the risk of Alzheimer's disease, they reported.
Another benefit of editing RNA is that it can be reversed. MIT researchers have shown in their study that they can use RESCUE to temporarily activate beta-catenin protein activation, which could be useful in wound healing.
RESCUE relies on another system developed by Broad and called RNA Editing for Programmable Replacement from A to I (REPAIR), which was reported by Zhang's team in 2017. This technology alters the Adenosine (A) nucleoside inosine (I), which could be useful in the treatment of diseases such as Duchenne muscular dystrophy and Parkinson's disease.
Several other research groups are working on RNA editing technologies, including a team from the University of California at San Diego (UCSD), which used a Cas9 system targeting RNA in laboratory models of myotonic dystrophy two years ago. Locana, a fallout from the UCSD that developed the technology, raised $ 55 million in May this year and is now tackling diseases such as Huntington's Lateral Sclerosis and amyotrophic sclerosis.
Broad's Zhang says that it will take a lot of work before being able to test RESCUE on people. In the meantime, it makes the tool accessible to the public via the Addgene repository so that other researchers can use it to study mutations related to the disease.
"To address the diversity of genetic changes that cause disease, we need a range of specific technologies to choose from," said Zhang in his release. "By developing this new enzyme and associating it with the programmability and precision of CRISPR, we have been able to fill a critical gap in the toolbox."
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