Small Molecules Seen to Ease Nerve Cell Deficits in Rett Lab Model

KW-2449 and VPA may be promising treatments for Rett syndrome, scientists say

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Scientists may have discovered promising treatments for Rett syndrome in two small molecules, called KW-2449 and VPA, each seen to ease nerve cell deficits — thereby potentially improving the flow of information between neurons — in a lab model of the disorder.

“These findings suggest that KW-2449 and VPA might be promising drugs for RTT [Rett] treatment,” investigators wrote.

That’s according to a study, “KW-2449 and VPA exert therapeutic effects on human neurons and cerebral organoids derived from MECP2-null hESCs,” that was published in the journal Stem Cell Research & Therapy.

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Researchers differentiated stem cells into neurons or 3D brain models

Nearly all cases of Rett syndrome are caused by mutations in the MECP2 gene, which contains instructions for making a protein (MeCP2) needed for the brain to develop normally.

How exactly those mutations prevent nerve cells (neurons) in the brain from working properly is unclear.

To know more, a team of researchers in China cut out both copies of the MECP2 gene from human embryonic stem cells, a type of cell from which other types of cells can develop.

Then, they differentiated the stem cells into neurons or cortical organoids, 3D models that recapitulate in the lab what happens in the developing human brain.

Neurons lacking the MECP2 gene (KO) did not increase as rapidly in number as did wild-type (WT) control neurons. There also were fewer of them testing positive for MAP2, a marker of neurons.

In line with these observations, KO neurons grew fewer and shorter neurites, which are the projections that extend outward from a neuron’s cell body. Neurites allow neurons to seek out other neurons and communicate with them.

These findings suggest that KW-2449 and VPA might be promising drugs for RTT [Rett] treatment

After 30 days, cortical organoids made out of KO stem cells had about as many neurons and neural precursor cells as control organoids. However, after 30 days more, KO cortical organoids contained fewer dividing neurons and more dead neurons. There were also significantly fewer of them testing positive for TUJ1, a protein that marks neurons from the earliest stages of differentiation.

“These results suggested that loss of MECP2 impaired neurogenesis in human cortical organoids,” the researchers wrote. Neurogenesis refers to the formation of new neurons.

Next, the researchers used a technique called patch-clamp to measure the current produced by a neuron as ions flow through its membrane (a cell’s border) during a nerve impulse.

Electrophysiological recordings revealed that KO neurons were not as good at sending impulses as control neurons, and also showed a reduction in excitatory synapses — the points of contact where nerve cells communicate. “Presumably, this is due to the decreased dendrite [neurite] length and neuronal complexity observed in MECP2 knockdown neurons,” the scientists wrote.

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A deep look into the genes that were switched “on” or “off” in KO versus control neurons revealed that many genes involved in the PI3K-AKT pathway were not as active in KO neurons as they were in control neurons.

This pathway is critical for how cells work because it helps them grow, divide, and remain alive. It is essential for the normal development of many of the body’s parts, including the brain.

To find out whether activating the PI3K-AKT pathway could rescue nerve cell deficits, the researchers tested two small molecules: KW-2449 and VPA. Of note, VPA, which is short for valproic acid, is approved for the treatment of seizures.

Treatment of KO cortical organoids with either KW-2449 or VPA rescued nerve cell deficits and reversed the gene activity changes seen in MECP2 KO organoids.

These findings suggest that “KW2449 or VPA can rescue brain organoids deficits caused by MECP2 loss-of-function,” the researchers concluded.