Potential cancer drug slows Rett’s progression, aids survival in mice
Investigative therapy targets immune cells, like microglia that support brain
Treatment with ADH-503, an experimental oral treatment for pancreatic cancer, was found to slow disease progression and prolong survival in a mouse model of Rett syndrome, according to a study that focused on how brain immune cells may play a role in Rett.
“I hope this work will ‘move the needle’ and bring the Rett community back to neuroimmunology,” Jonathan Kipnis, PhD, a professor at Washington University School of Medicine in St. Louis, Missouri, who not involved in this study, said in a press release from the University of California San Diego.
The study, “Human microglial cells as a therapeutic target in a neurodevelopmental disease model,” was published in Stem Cell Reports.
Study into how Rett-causing mutations affect microglia, immune cells of brain
Almost all Rett syndrome cases are caused by mutations in the gene MECP2. This gene provides instructions to make the MeCP2 protein, which helps to regulate the activity of other genes within cells.
It’s well established that MECP2 mutations affect the function of neurons, the long, wire-like cells that send electrical signals in the nervous system. In particular, MeCP2 protein dysfunction is thought to contribute to problems with the formation of synapses, which are the connections between individual nerve cells.
But the MECP2 gene also is expressed by other cells in the nervous system, and comparatively little is known about how Rett-causing mutations affect the activity of these other cells.
Scientists at the University of California San Diego School of Medicine conducted a battery of experiments to investigate how these mutations affect microglia.
Microglia are the resident immune cell of the brain, playing a key role in defending the brain against infectious threats. These specialized cells also act as the “janitors” of the nervous system — working through a process called phagocytosis to gobble up and destroy unneeded molecular waste and debris.
Results of their experiments showed that, when microglia carry a Rett-causing mutation in the MECP2 gene, their ability to perform phagocytosis is impaired.
“If the brain’s ‘janitors’ are not working, problems start to arise,” said Alysson Muotri, PhD, the study’s senior author and director of the university’s stem cell program.
ADH-503 being tested in cancer for ability to modulate immune cell activity
The scientists further showed that, when MECP2-mutant microglia are grown in a culture together with genetically normal neurons, the neurons’ ability to form synapses is impaired. Microglia with MECP2 mutations “are not as good at pruning synapses and shaping the neural network — they don’t do a good job,” Muotri said.
These findings imply that the problems with synapse formation that characterize Rett syndrome are not just because of dysfunction in neurons themselves, but in other cells of the brain as well.
“Our results suggest that microglia impact the function and maturation of neuronal cells,” the researchers wrote, noting that this function of microglia has been “previously underappreciated.”
Based on these data, the researchers wondered if targeting microglia might be a meaningful strategy for treating Rett syndrome. As a proof of concept for this idea, they screened various therapeutic compounds, looking for medications that can boost phagocytosis and synapse-forming abilities in MECP2-mutant microglia.
Screenings zeroed in on ADH-503, also called GB1275. This experimental medication is being tested as a cancer treatment because it is able to modulate the activity of immune cells by activating a protein called CD11b. Notably, the gene that provides instruction to make the CD11b protein is known to be regulated by MeCP2.
After identifying ADH-503 as a potential treatment, the researchers tested the compound in a mouse model of Rett syndrome. Treated mice were found to have significantly slower disease progression, and they lived about 40% longer on average than mice who didn’t receive the treatment.
Researchers stressed that ADH-503 showed beneficial effects even when the treatment was started after disease progression had already set in. This point is important because people usually are not diagnosed with Rett until after the disease has begun to progress. They noted, however, that their experiments were in male mice, whereas Rett syndrome predominantly affects females, so further research is needed to verify and expand on the results.
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