Gene therapy ‘sponge’ revives healthy gene in Rett syndrome
Blocking miR‑106a RNA molecule called a 'feasible therapeutic strategy'
Blocking a small RNA molecule that helps control whether certain genes are switched on or off reactivated the healthy copy of the MECP2 gene in a mouse model of Rett syndrome, increasing lifespan and activity, and improving breathing.
While blocking miR‑106a appears to be “a feasible therapeutic strategy,” before it can be advanced to clinical testing in patients, more research is needed to study its safety, therapeutic potential, and appropriate dosing, the study’s researchers wrote in “Targeting microRNA-dependent control of X chromosome inactivation improves the Rett syndrome phenotype.” The study was published in Nature Communications.
Rett syndrome is a genetic disease that mostly develops in girls. It’s chiefly caused by mutations in the MECP2 gene, which is found in the X chromosome. In females, one X chromosome in each cell is randomly switched off during development in a process called X chromosome inactivation. However, in Rett syndrome, the healthy copy of the MECP2 gene is often on the inactivated X chromosome, leaving only the mutated copy active. This causes a range of symptoms, from loss of speech and loss of hand function to breathing problems and seizures.
Here, researchers screened female fibroblast cells to identify small RNA molecules that control gene activity, or microRNAs, that are involved in X chromosome inactivation. One, called miR‑106a, stood out as an important regulator of this process.
Reviving healthy MECP2 gene copy
In X chromosome inactivation, a long RNA molecule called Xist covers the inactive X chromosome and is linked to proteins and chemical marks that modify DNA packaging. These modifications keep the genes on that chromosome switched off. The researchers found that miR‑106a interacts with a specific region of Xist, helping it maintain genes in an off state.
When miR‑106a was depleted, its interaction with Xist was disrupted. This made Xist unstable. The researchers then tested if blocking miR‑106a could reactivate the healthy copy of the MECP2 gene in a mouse model of Rett syndrome.
They used a viral vector given soon after birth to mice to introduce a “sponge” molecule that binds to and blocks miR‑106a. This resulted in a modest, but significant, decrease in Xist levels in their brain and an increase in the MeCP2 protein.
The treated mice lived longer, were more active, explored more, and had more regular breathing than untreated mice. On a genetic level, only about 8% of other genes on the X chromosome showed activity changes of more than 1.5 times.
“Consistent with our results, multiple studies have previously reported that the general [X chromosome] reactivation does not cause robust gene expression changes or in vivo consequences,” wrote the scientists, who said further studies are warranted because they “only measured the effects of miR106a depletion on the expression of selected genes from [X chromosome inactivation].”
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