Visual problems in Rett may be reversible, mouse study shows
Partly restoring MeCP2 production reverses disrupted signaling
Written by |
Partially restoring the production of MeCP2, the protein deficient in people with Rett syndrome, reversed abnormal nerve signaling in the brain’s visual cortex, improving visual acuity in a mouse model, a study found.
“This underscores the transformative potential of genetic medicine-based therapies in [Rett], suggesting that even partial restoration of MeCP2 can meaningfully improve sensory processing and quality of life for patients,” the researchers wrote.
The study, “Visual Recovery Reflects Cortical MeCP2 Sensitivity in Rett Syndrome,’ was published in Annals of Clinical and Translational Neurology.
Rett syndrome is caused in most cases by genetic mutations that disrupt the production of MeCP2, a protein abundant in nerve cells that influences brain development and function. Symptoms of Rett, which primarily affects girls, include developmental delays and regression, motor skill loss, and communication difficulties.
People with Rett can also experience sensory impairment, including reduced visual and spatial acuity, and declines in nerve cell signaling related to vision and hearing.
MeCP2 and vision
Researchers in the U.S. and Italy used a Rett mouse model in which MeCP2 production could be turned on and off to investigate early changes in visual symptoms associated with MeCP2 deficiency. The team focused on the impact of restoring MeCP2 production to understand how gene therapies may help reverse Rett-related visual disturbances after symptom onset.
At 30 days of age, before the onset of Rett symptoms, tests showed that nerve signaling in the visual cortex (the part of the brain that processes visual information) was disrupted in male Rett mice. Even so, the central relay station for visual information traveling from the eye to the visual cortex, called the dorsal lateral geniculate nucleus, was unaffected.
MeCP2 production was switched on when the mice were 35 days old, increasing MeCP2 protein levels in nerve cells to about 60% of those in healthy mice by day 105. This extended survival, halted Rett progression, and prevented the emergence of new symptoms.
Boosting MeCP2 also reversed deficits in nerve signaling within the visual cortex. And it improved spatial acuity (the ability to distinguish fine details), which is impaired in Rett patients, and partially rescued abnormalities in the electrical activity of the brain’s visual processing systems. Still, increasing MeCP2 did not rescue the thinning of the outer layer of the brain (cortex) observed in male Rett mice.
Even in fully symptomatic female Rett mice in advanced stages of the disease, MeCP2 reactivation was sufficient to improve visual acuity after six weeks.
“A late and partial activation of MeCP2 expression starting well after cortical deficits arise was still sufficient to reverse [visual cortex] functional abnormalities and improve sensory processing in Mecp2-deficient mice,” the team wrote.
The study’s results “highlight the remarkable sensitivity of cortical circuits to MeCP2 expression in both developing and mature brain,” the researchers wrote. “Importantly, restoring just 60%-70% of MeCP2 protein levels was sufficient to rescue sensory functions, even after the onset of regression.”
