RNA rewriting improves respiration and survival in Rett mice | Domain

RNA rescue: Rett syndrome model mice treated with RNA-modifying viruses recovered MECP2 in the brainstem (lower right).

A new study shows that mice with a genetic mutation linked to Rett syndrome breathe more easily and live longer after treatment with RNA editing. study. The treatment partially restores expression of the mutated gene in the brainstem, which controls basic functions such as breathing.

The method is likely designed for use in people with Rett syndrome, says the lead researcher Jill Mandel, professor of biochemistry and molecular biology at Oregon Health & Science University in Portland. Mice have a mutation in the MECP2 gene involving the exchange of a single DNA letter from guanosine (G) to adenosine (A), which mirrors the mutation observed in humans.

right syndrome It usually arises from mutations in MECP2It is a gene located on the X chromosome that mainly affects girls. His early signs, including regression in language and social skills during childhood, overlap with autism. Children with this condition also have breathing problems, including hyperventilation and breath holding.

The new work suggests that it may be possible to alleviate these breathing problems by correcting the mutation in MECP2 mRNA, the single-stranded version of the gene that conveys instructions to make the MECP2 protein.

He says, “It’s exciting.” Joshua Rosenthal, a senior scientist at the Marine Biology Laboratory in Woods Hole, Massachusetts, who was not involved in the work. Rosenthal’s laboratory was a pioneer in RNA editing technology used in the study, but they did not test it on animals or humans.

“Taking it from this basic concept and seeing it actually transmitted by a virus in a mouse, correcting the mutation and seeing the physiological output and survival — it’s fantastic,” Rosenthal says.

MAndel and her team injected male Rett mice with two harmless viruses: one expressing an enzyme that edits RNA, and the other containing an engineered RNA sequence that directs the enzyme to the MECP2 mutation. (Female MECP2 mice had a working copy of the gene in some of their cells, which would have complicated the analysis.)

The editing enzyme replaces a functional group in stray A, turning it into I (inosine), which the cell’s protein-making machinery reads as G. One of two others that can be similarly manipulated by editing the target RNA, Mandel and her team note in the Rett Research Database.

About half of the treated mice lived to 16 weeks of age, compared to 12 weeks in the untreated mice. The oldest treated mouse lived 27 weeks, while all untreated mice died by 16 weeks of age.

Of all the areas of the brain affected by treatment, the brainstem was the most effective in restoring MECP2 expression, RNA sequencing showed, and the treated mice no longer had prolonged pauses in breathing – effects that lasted at least four weeks, This is the age at which the researchers tested the efficiency of editing. By contrast, injecting wild-type mice with viruses had no effect on their survival, indicating that the modification targets only the mutated RNA sequence.

Work appeared in August in Proceedings of the National Academy of Sciences.

One advantage of this strategy is that it has lower risks with off-target modification compared to DNA modification Jean Marino Ramirezprofessor of neurosurgery and pediatrics at the University of Washington in Seattle, who was not involved in the study.

Plus, it’s more effective than editing DNA in cells, such as nerve cells, that don’t divide, Rosenthal says. The fact that the effects last for weeks is exciting, he says, because it shows that once the virus begins modifying its RNA, the process continues for some time.

The main unknown, Mandel says, however, is how long it lasts.

THe freed mice that died sooner than wild mice, none of which had died by the end of the 28th week. Mandel and her team still don’t know why.

Part of the problem, Mandel says, is that animals’ behaviors depend on circuits distributed across the brain. For successful editing, the RNA must be available to the guide virus, and delivery of the RNA-editing virus to each region implicated in a particular behavior is challenging. For this reason, improving breathing, which is controlled by the brainstem, is a simpler goal than reinforcing social behaviors, she says.

“It seems likely that the virus, the stimuli in the virus that express the release load, or both, are not yet optimal for reaching the correct cell types or sufficient cells to prevent early lethality,” Mandel says.

Mandel says the team plans to tweak its approach to see if they can target other MECP2 mutations. They also plan to use female mice in the next round of experiments, because their longer lifespan should allow researchers to track how long the editing effects last.

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