Treatment Targeting miR-134, RNA Molecule, Limits Seizures in Mice

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Lower the levels of a small RNA molecule called miR-134 was shown to protect against seizures for both old and young mice in a model of Angelman syndrome in a study.

The study, “AntimiR targeting of microRNA-134 reduces seizures in a mouse model of Angelman syndrome,” was published in Molecular Therapy Nucleic Acids.

When a gene is “read” to create a protein, the genetic sequence is transcribed into a temporary molecule called messenger RNA (mRNA), which is shuttled to the cell’s protein-making machinery for translation into a protein.

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MicroRNAs, or miRNAs, are a separate class of small RNA molecules. miRNAs can bind to mRNA molecules with specific sequences, which stops the mRNA from being used to make protein. By controlling levels of both mRNA and miRNA, cells can fine-tune exactly how much of different proteins are made.

Angelman syndrome is caused by mutations, or variants, in the UBE3A gene, which leads to the absence or malfunction of the encoded enzyme called ubiquitin-protein ligase E3A in the nervous system.

Recent research has shown that the UBE3A gene has a specific spot in its genetic sequence where a miRNA called miR-134 could potentially bind. Although UBE3A had not been confirmed as a target of miR-134 regulation, prior studies in mice indicated that reducing miR-134 levels could prevent seizures, a characteristic Angelman symptom.

“This suggests a mechanistic link between miR-134 and the molecular pathogenesis [disease development] of [Angelman syndrome], raising the possibility of a therapeutic approach targeting this miRNA,” the researchers wrote.

The team, led by scientists in Ireland, conducted a series of experiments in mouse models of Angelman syndrome.

Investigators first measured levels of miR-134, as well as several genes that the miRNA is known to regulate, in the mice’s brains. While some small differences were noted, the results broadly showed that miR-134 and its target genes are similarly active in Angelman as in wild-type mice.

They then tested the effects of treatment with a molecule that blocks miR-134 activity, called an antimiR. In one mouse model, antimiR treatment normalized scores on the open field test, a measure of anxiety and exploratory behaviors in mice.

“Movement and anxiety defects are a consistent phenotype [trait] in [Angelman] mice,” the researchers wrote, adding that the result “supports the targeting of miR-134 to alleviate certain phenotypes in [Angelman syndrome].”

Experiments in another model, where a specific set of sounds would trigger a seizure in the mice, showed that antimiR treatment protected against the sound-induced seizures — two antimiR-treated mice had no seizures at all, and seizure severity was markedly reduced in the others compared to untreated mice.

Initial experiments to test the effect of antimiR on seizures were in relatively young mice. Additional tests using older animals showed generally comparable results, with antimiR protecting against seizures.

“Taken together, these results indicate silencing miR-134 has anti-seizure effects in [Angelman syndrome] mice and this extends into adulthood,” the researchers concluded.

The scientists noted that genetic therapies aiming to normalize UBE3A activity have generally not been effective for controlling seizures in older mice with Angelman. This is likely because the UBE3A gene is necessary for certain stages of development; once those stages are past, activating the gene cannot fully reverse damage that has occurred in the meantime.

“Targeting miR-134 does not appear to be as age-restricted, offering a possible advantage over current gene therapy rescue approaches,” the researchers wrote.

As a proof-of-concept for the use of this approach in people with Angelman syndrome, the researchers also demonstrated that antimiR treatment could lower miR-134 levels in nerve cells derived from a patient.