For the first time, scientists have repaired a mutation in mice that underlies Rett syndrome, partially restoring lost protein function, a recent study reports.
The findings provide proof of principle that a technique called RNA editing might prove an effective therapeutic strategy in humans, according to the researchers involved in the study.
Conducted by scientists at Oregon Health and Science University, the study, “In Vivo Repair of a Protein Underlying a Neurological Disorder by Programmable RNA Editing,” was published in the journal Cell Reports.
“The study is the first example of RNA editing in a mouse model of a neurological disease, and therefore a considerable step forward in the potential of RNA editing becoming a therapeutic for Rett Syndrome,” Monica Coenraads, executive director of Rett Syndrome Research Trust, said in a press release. The organization provided funding for the research, along with the National Institutes of Health.
Mutations in the MECP2 gene are the most common cause of Rett syndrome. This gene provides instructions for making the MeCP2 protein, which controls the activity of other genes and is important for nerve cell communication.
Using a mouse model of Rett, the researchers used RNA editing to correct a mutation in MeCP2 by rewriting the RNA to code for a healthy protein. Genetic instructions for making a protein begin as DNA and are transcribed into RNA, which the cell uses to construct proteins.
Building on early success in the lab dish, the team wanted to find out whether it was possible to edit the MECP2 RNA in nerve cells of mice, which types of neurons they could edit, and whether doing so restored MeCP2 protein function.
To address these questions, the investigators used a harmless adeno-associated virus carrying instructions for an editing enzyme — called an “editase” — and a guide RNA to recognize the faulty gene section. The viral vector was delivered directly into the hippocampus, an area of the brain key for memory and learning.
Specifically, the mice carried a mutation consisting of a change in a single nucleotide, the building blocks of DNA. The four types of nucleotides are known by their first letter — A, U, G, and T. In the mouse model of Rett, a G (guanine) was replaced by A (adenine). According to the team, a strategy aimed at this specific change could address about 40% of all known mutations in Rett syndrome.
Results showed that the injected editase repaired approximately half of the mutant RNA in three types of neurons found in different regions of the hippocampus. The approach also restored healthy function in the resulting MeCP2 proteins.
“It is encouraging that this RNA editing approach seems to be efficacious in different types of neurons in the brain,” said Gail Mandel, PhD, the study’s senior author.
While overall successful, the approach did cause off-target edits in genes other than MECP2, but with unknown effects and no harm to mice.
“This study demonstrates that programmable RNA editing can be utilized to repair mutations in mouse models of neurological disease,” the investigators wrote in the study.
“In the next set of experiments, we will administer the virus by blood, so that the entire brain is subject to editing. This will allow us to monitor whether there is any amelioration of Rett symptoms in the mice,” Mandel said.
The team will also seek answers to just how much MeCP2 RNA needs to be repaired and in how many cells to have a therapeutic effect. They also hope their study will spur others to safely improve RNA editing efficiency so that the approach can become a treatment strategy in not only Rett syndrome but other conditions as well.
“There are many bright and determined investigators working on these problems,” Mandel said. “My hope is this paper will stimulate these creative minds even further. We are trying to take advantage of what’s happening in the field in real time and apply the emerging optimizations to Rett and other neurological diseases.”
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