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Reprogrammed neurons reveal drug lead for incurable childhood disease

Dolmetsch.jpgUsing the power of reprogrammed stem cells, researchers in California have found a potential new drug lead for a devastating childhood disease that currently lacks good treatment options.

“[The] work is very inspiring,” says Alysson Muotri, a neurogeneticist at the University of California-San Diego who was not involved in the study. “It is a beautiful and elegant manuscript that carefully describes several defects associated with Timothy syndrome brain cells and offers therapeutical opportunities for these families.”

Timothy syndrome is a rare genetic disease marked by mutations in a gene encoding a calcium channel subunit. Children with this genetic defect often develop physical malformations in their hearts and fingers as well as severe neurological problems resembling autism. Doctors typically administer drugs to improve the irregular heart rhythms associated with Timothy syndrome, but there are no therapies available to reverse the developmental irregularities triggered by the disease. So, a team led by Ricardo Dolmetsch at the Stanford University School of Medicine turned to cellular reprogramming to find new drug leads.

The researchers harvested skin cells from a handful of kids with Timothy syndrome and turned them into induced pluripotent stem (iPS) cells. They then coaxed the cells to form neurons (pictured here), and tested a number of known calcium blocking agents for their therapeutic activity. Reporting today in Nature Medicine, they showed that neurons derived from people with Timothy syndrome expressed certain neurotransmitters abnormally, but this trait could be corrected by roscovitine, a drug currently in clinical trials for the treatment of various types of cancer. Roscovitine — which is being developed by Cyclacel Pharmaceuticals of Berkeley Heights, New Jersey under the brand name Seliciclib — also restored cellular signaling in heart muscle cells derived from the same iPS cells, Dolmetsch’s team reported earlier this year in Nature.


“It’s a very promising drug lead,” says Dolmetsch. “The problem is that it’s a cancer drug. And even though it’s relatively safe, this gives the pediatricians some pause.” So, the next step, he says, is to find drugs that similarly block calcium channels but don’t present the attendant side effects experienced by participants in cancer trials, including nausea, vomiting, low potassium levels and liver abnormalities. After that, “it would be of great interest to see the translatability of these findings in vivo, first in a mouse model followed by human studies,” remarks Igor Splawski, a researcher at the Novartis Institutes for Biomedical Research in Cambridge, Massachusetts, who conducted much of the pioneering molecular work on the syndrome together with the University of Utah’s Katherine Timothy, for whom the disease is named.

Intriguingly, however, studies in mouse models might never have flagged roscovitine as a potential therapeutic agent for the disease in the first place. To provide additional support for the cellular phenomena observed in the stem cell-derived neurons, Dolmetsch’s team also created mice expressing the defective calcium channel found in people with Timothy syndrome. These mice had abnormal gene expression patterns in parts of the brain cortex not seen in the simpler cellular model. Yet unlike the human neurons, the genetically engineered animals did not display an excess of tyrosine hydroxylase, an enzyme involved in dopamine production that is modulated by roscovitine.

Muotri, who has developed iPS cells for Rett syndrome, another autism spectrum disorder, says that observations like these drive home the importance of using cellular reprogramming to study neurological diseases, as lab animals don’t always recapitulate all the defects observed in human neurons. “To me, this represents the value of the human model, especially in diseases such as autism,” he says.

Tune in to the Nature Medicine podcast next month for a full interview with Dolmetsch about the work. Or subscribe to the show through iTunes for automatic episode updates.

Image of iPS cell-derived neurons from a child with Timothy syndrome courtesy of the Dolmetsch lab at Stanford University.

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