We've seen the powerful ways the CRISPR gene-editing tool could bring about better health outcomes by targeting and replacing specific pieces of DNA, but scientists at the University of California San Diego (UCSD) have been exploring a different approach. By using the technique to target RNA instead, the researchers have demonstrated an ability to destroy toxic accumulations of this molecule, which could pave the way for new treatments for muscular dystrophy and related conditions.
The new research builds on a study published in 2016, in which UCSD scientists showed that the CRISPR tool could be used to target RNA in live cells. RNA acts as the messenger service, communicating information about our genes to the cell’s machinery for producing proteins, and where it is located and how it travels through the cell can determine how well this important function is carried out.
When the RNA doesn’t follow the correct path or ends up in a location it is not supposed to be, it can cause problems. Research has linked misplaced RNA to a range of conditions including autism and cancer, so the ability to target it in live cells was an important step forward.
When CRISPR is used to target DNA, scientists use a piece of RNA designed to mimic the sequence of the target gene, which guides an enzyme called Cas9 to the desired location. Once there, the enzyme cuts the DNA and inactivates the gene, a break that can then be replaced with new version.
The UCSD team, along with collaborators at Locanabio, Inc. and the University of Florida, was able to make alterations to this system, designing a short nucleic acid that works with the guide RNA to seek out an RNA molecule instead, a technology the scientists call RNA-targeted Cas9. The scientists have now turned their attention to developing new treatments for myotonic dystrophy type 1, the most common type of adult-onset muscular dystrophy.
Sufferers of this disease inherit repeating DNA segments that cause a toxic accumulation of repetitive RNA, which causes the deterioration of muscles and increasing weakness characteristic of the disease. The scientists set out to explore whether their RNA-targeted Cas9 could be used to clear away this troublesome waste.
The experiments were carried out on mouse models of the disease, with the rodents injected with a new version of the gene therapy involving virus vectors and the RNA guide to target the repetitive RNA. The team found that just one dose could help rid the animals of the toxic RNA buildup and reversed nearly all symptoms of myotonic dystrophy on a sustained basis.
According to the team, this demonstrates that its RNA-targeted Cas9 gene therapy technique could prove to be powerful way to treat myotonic dystrophy type 1. And this toxic buildup of RNA has been linked to a number of other incurable diseases, so the technique may have even greater potential.
“Many other severe neuromuscular diseases, such as Huntington’s and ALS, are also caused by similar RNA buildup,” says senior author Gene Yeo. “There are no cures for these diseases.”
The research was published in the journal Nature Biomedical Engineering.
