Scientists have identified two compounds that were able to rescue nerve cell defects caused by mutations in the MECP2 gene — the most common cause of Rett syndrome — in patient-derived cellular models, including “mini-brains.”
These findings support the launch of a pilot clinical trial evaluating these compounds — nefiracetam and PHA-543613 — in Rett patients, according to the researchers.
Notably, nefiracetam has already undergone testing in humans for conditions such as dementia, post‐stroke apathy, and major depressive disorder, while PHA-543613 was shown to have neuroprotective effects in a rat model of Huntington’s disease.
The study, “Pharmacological reversal of synaptic and network pathology in human MECP2‐KO neurons and cortical organoids,” was published in the journal EMBO Molecular Medicine.
“The gene mutation that causes Rett syndrome was discovered decades ago, but progress on treating it has lagged, at least in part because mouse model studies haven’t translated to humans,” Alysson R. Muotri, PhD, the study’s senior author, said in a university press release.
“This study was driven by the need for a model that better mimics the human brain,” added Muotri, who is a professor of pediatrics and cellular and molecular medicine at University of California San Diego’s School of Medicine.
Muotri and his colleagues established a new therapy screening pipeline made up of three increasingly complex cellular models of Rett syndrome based on patient-derived induced pluripotent stem cells (iPSCs).
iPSCs are generated from fully matured cells that are reprogrammed back to a stem cell-like state, where they can give rise to almost every type of human cell. As such, they can be genetically modified to carry known disease-causing mutations or derived directly from patients to be used as cellular models that mimic the disease’s genetic and clinical diversity.
First, the researchers developed two lines of MECP2-mutated nerve cells: one derived from iPSCs from a Rett patient with an MECP2 mutation, and the other from human cells genetically modified to carry a known disease-causing MECP2 mutation.
By comparing these nerve cells with healthy cells, the team was able to identify Rett syndrome hallmarks at the cellular level. These included changes in several features involved in nerve cell communication: synapse function, activity of genes regulating synapse health and neurotransmitter production, and calcium levels.
For reference, synapses are the sites of transmission of chemical messengers (neurotransmitters) and electrical signals between nerve cells.
The team then tested 14 pharmacological compounds whose mechanisms of action were known to counteract the observed nerve cell abnormalities. This screening resulted in the identification of nefiracetam and PHA 543613, which were seen to reverse nearly all deficits seen in MECP2‐mutated nerve cells without affecting healthy nerve cells.
These compounds were then validated in two newly developed 3D cellular models of Rett syndrome: MECP2‐mosaic neurospheres and brain-like organoids, or “mini-brains.”
The first model mixes mutated and healthy nerve cells derived from iPSCs to mimic the mosaic pattern typically seen in female patients due to a process called X‐chromosome inactivation.
The mini-brains are even more complex, composed of different types of nerve cells that can more fully mimic the properties and cellular interactions of the human brain than animal models. Muotri’s team had previously optimized brain-like organoids to closely mimic aspects of human fetal neurodevelopment.
Results in these Rett syndrome 3D models showed that nefiracetam and PHA 543613 restored calcium levels, activity of synapse- and neurotransmitter-related genes, neurologic network activity, and electrical signaling.
Both compounds, which are taken orally, “exhibited potential to partially rescue the synaptic defects caused by MeCP2 deficiency and are viable candidates for clinical trial,” the researchers wrote.
The team also hopes that this therapy screening platform will be used in the future to test a larger number of compounds and move them to clinical trials.
“There’s a tendency in the neuroscience field to look for highly specific drugs that hit exact targets, and to use a single drug for a complex disease, said Muotri, who is also the director of University of California San Diego’s stem cell program and a member of the Sanford Consortium for Regenerative Medicine.
“But we don’t do that for many other complex disorders, where multi-pronged treatments are used,” he added. “Likewise, here no one target fixed all the problems. We need to start thinking in terms of drug cocktails, as have been successful in treating HIV and cancers.”
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