Mature nerve cells may tolerate higher MeCP2 levels, new study suggests
Findings could inform future Rett gene therapy dosing strategies
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Abnormally high activity of the MECP2 gene can profoundly disrupt immature brain cells during early development, but appears to have only modest effects in mature nerve cells, according to a new study.
The findings may have important implications for the development of gene therapies for Rett syndrome, which is caused mainly by mutations that reduce the activity of the MECP2 gene. Rett gene therapies currently in development aim to carefully constrain MECP2 activity to avoid raising it too high, but these preclinical data suggest mature nerve cells may tolerate higher MECP2 activity than previously thought.
The study, “MeCP2 gene dosage-dependent neurodevelopmentally restricted defects arise by aberrant activation of cell fate-determining bivalent genes,” was published in Nature Communications.
Why MeCP2 dosing matters in Rett
The MECP2 gene provides instructions to make the MeCP2 protein, which helps coordinate which genes are turned on or off in nerve cells. In Rett syndrome, too little functional MeCP2 protein disrupts normal nerve cell activity, ultimately giving rise to Rett symptoms.
Since too little MECP2 activity is the main cause of Rett syndrome, gene therapies for Rett syndrome broadly aim to increase the gene’s activity to normal levels. Two experimental Rett gene therapies designed to increase MECP2 activity are currently in pivotal testing.
Both therapies aim to increase MECP2 activity, but they also include built-in systems intended to prevent harmful overactivity. This is because too-high MECP2 activity can also cause neurological problems. In particular, MECP2 duplication syndrome is caused by an extra copy of the gene and is associated with neurodevelopmental delay, low muscle tone, and epilepsy. As such, scientists have long thought that developing a gene therapy for Rett will require a careful balancing act to increase MECP2 activity enough to help, but not so much that it becomes harmful.
But even though avoiding too-high MECP2 activity has been a key goal of Rett gene therapy, prior mouse studies found that high-dose viral delivery did not cause neurological problems directly linked to MeCP2 overproduction. A team of scientists in Italy set out to explore this apparent paradox using mouse and human neural cells, as well as mouse models.
The researchers found that too-high MECP2 activity leads to profound gene dysregulation in neural progenitor cells, which are immature cells that help form the brain and other parts of the nervous system during early development. When MECP2 activity is too high in early development — as occurs in MECP2 duplication syndrome — these immature cells may be pushed toward premature or altered nerve cell development.
Mature nerve cells showed fewer changes
By contrast, in nerve cells that are already fully mature, the researchers found that abnormally high MECP2 activity had relatively little impact on gene activity and cell function.
“We report that Mecp2 overexpression elicits profoundly divergent outcomes depending on the cellular context, with NPCs [neural progenitor cells] displaying significantly greater sensitivity than fully differentiated [nerve cells],” the researchers wrote.
Further tests revealed a possible biochemical basis for this difference. The MeCP2 protein normally helps regulate gene activity by binding to specific sites in a cell’s DNA. In immature neural progenitor cells, MeCP2 protein levels are relatively low, so many of these DNA sites are not already occupied by the protein. Increasing MECP2 activity in these cells raises MeCP2 protein levels, allowing more of the protein to bind to DNA and disrupting the activity of many genes involved in development.
By contrast, mature nerve cells normally have much higher MeCP2 protein levels. In these cells, many target DNA sites are already occupied by the cell’s own MeCP2 protein. The added MeCP2 also showed weaker DNA binding and was broken down more quickly, limiting its effect on gene activity.
Overall, these preclinical findings suggest mature nerve cells may be more tolerant of increased MeCP2 dosage than previously thought. That could help inform future Rett gene therapy strategies.
“Our findings significantly advance our understanding of Mecp2 function and have important implications for gene therapy strategies for Rett syndrome,” the researchers concluded, adding that these findings “challenge the notion that Mecp2 dosage must be narrowly constrained, supporting the possibility of more flexible and potentially higher dosing strategies in therapeutic settings.”
The researchers noted that more work is needed to understand long-term effects and whether other cell types respond differently.
