Broad scientists oust Alzheimer’s risk gene in a lab dish by revising DNA

Photo Courtesy of Stephen Dixon/the McGovern Institute

The CRISPR family enzyme CAS13 (pink) uses a special guide (red) to target RNAs in the cell (blue). Broad Institute scientists used a new model of CRISPR, CAS13, to try to eliminate a genetic risk for Alzheimer’s disease, they report in the journal Science.

With a newly adapted CRISPR tool, researchers out of the Broad Institute of MIT and Harvard, have stamped out an Alzheimer’s threat in cells by revising RNA, rather than permanently editing DNA.

The findings were reported in the July 11, 2019 issue of the journal Science.

Feng Zhang, PhD and colleagues illustrated the promise of the new CRISPR platform, CAS13, by deactivating the APOE4 risk gene and changing it to APOE2, the rarer variant (which is protective and may actually decrease a person’s risk for Alzheimer’s: Science). Long viewed as one of the biggest risk factors for Alzheimer’s – APOE4 is also associated with the most common form of the disease.

Because protein-coding RNA is transcribed from genomic DNA, this technique offers the potential to correct disease-causing mutations at the RNA level without the possible risks of making permanent changes to the genome. In addition, in some cell types, particularly postmitotic cells such as neurons, it is difficult to edit genomic DNA using earlier CRISPR approaches. Therefore, CAS13 represents a potential new strategy to treat devastating diseases that affect the brain, including Alzheimer’s.

The new advance, called RESCUE for RNA Editing for Specific C to U Exchange, builds on REPAIR, a technology developed earlier by Zhang and his team that changes adenine bases into inosine in RNA. The scientists took the REPAIR fusion and evolved it in the lab until it could change cytosine to uridine.“Development of RESCUE demonstrates the power of protein engineering of natural processes,” said Deerfielder Bob Jackson, MD. “The ability of RESCUE to edit from C to U increases the number of pathogenic mutations targetable by RNA editing. It also adds capacity to potentially edit important signaling residues.”

CRISPR refers to Clustered Regularly Interspaced Short Palindromic Repeats that occur in the genome of certain bacteria, from which the system was discovered. Often thought of as “molecular scissors”, the CRISPR technology enables researchers to remove, add or alter specific DNA and RNA sequences in the genome of higher organisms, with the goal of curing disease.

The Broad has been a Deerfield collaborator since 2017: Broad Institute and Deerfield Management launch innovative partnership to tackle serious unmet medical needs

Adapted from MIT news release