Neural precursor cells found to ease Rett-like symptoms in mouse study
Transplant was able to reduce mortality, restore memory and motor functions
Brain transplant of neural precursor cells, which are self-renewing cells that give rise to neurons and other cells in the brain, can reduce mortality, and restore memory and motor functions in a mouse model of Rett syndrome, according to a recent study.
Genetic analysis revealed these cells may be able to activate genes related to communication between immune cells using a particular cytokine protein known as interferon-gamma. Direct injections into the brain of interferon-gamma was also found to reduce Rett-like symptoms in mice.
“Willing to respond to the unmet need of identifying novel therapies for RTT [Rett], we proved the therapeutic potential of [neural precursor cells] and we identified Interferon-[gamma] as a possible novel healing molecule for RTT,” researchers wrote in the study “Neural precursor cells rescue symptoms of Rett syndrome by activation of the interferon γ pathway,” which was published in EMBO Molecular Medicine.
Rett syndrome is a neurological disorder that causes regression or decline of motor and communication skills starting between the ages of 6 and 18 months. Rett primarily affects girls, leading to symptoms such as learning difficulties, repetitive hand motions, and seizures.
Rett is chiefly caused by mutations in the MECP2 gene that impair the function of the MeCP2 protein, which is important for brain development and functioning. Impaired communication between nerve cells through connections known as synapses and increased brain inflammation are believed to contribute to Rett symptoms.
Treatment Daybue believed to promote health of synapses, lower inflammation
The only approved treatment for Rett syndrome in the U.S. is Daybue, which is believed to promote the health of synapses and lower inflammation.
Cell therapy with transplant of neural precursor cells into the brain is being widely investigated as a treatment for many neurological disorders. Once in the brain, neural precursor cells can replace damaged cells and interact with immune cells.
Last year, a small clinical trial in multiple sclerosis patients showed transplant of neural precursor cells was well tolerated, with promising signs on markers of brain inflammation.
“[Neural precursor cell] transplantation has already been proved safe and efficacious in many neurological disorders but a comprehensive study of [neural precursor cell] efficacy in RTT is lacking,” the researchers wrote.
In the new study, researchers in Italy tested the therapeutic potential of neural precursor cell transplant by injecting the cells into the brain of mice with no MeCP2 function.
Rett mice that did not receive neural precursor cells had shorter lifespans than the treated mice. Their median lifespan was 70 days, while the treated mice had a median lifespan of 94 days.
In addition, Rett mice exhibited motor- and memory-related problems and had overall worse well-being relative to control mice. However, Rett mice broadly improved with neural precursor cell transplant.
Neural precursor cell transplant led to improvements in motor issues, memory
Around 12 days after the procedure, Rett mice showed improvements in motor issues, with fewer impairments in mobility, gait, tremors, and paw clasping. These mice also performed better on memory after receiving neural precursor cells.
To understand why Rett mice exhibited these benefits, the scientists genetically analyzed the brains of the mice, and found that many genes related to immune functioning were altered in the Rett mice that had received cell therapy.
In particular, the researchers found genes related to a protein used by immune cells to communicate, called interferon-gamma, were lower in Rett mice than in control mice. However, after the Rett mice were treated with neural precursor cells, this interferon-gamma pathway was activated.
The investigators then injected interferon-gamma into the brains of Rett mice to see whether it could reduce Rett-like changes. Beginning one day after a single injection with interferon-gamma, treated Rett mice performed significantly better on motor- and memory-related tasks.
Additional experiments with MECP2-mutant neurons in a dish suggested both neural precursor cells and interferon-gamma reduced problems with synaptic communication.
“Although we are aware that many other factors might mediate the beneficial effects of [neural precursor cells] on RTT models, we believe that a pre-clinical study assessing the therapeutic efficacy of a prolonged treatment of [interferon-gamma] in RTT deserves further investigations,” the researchers concluded.
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