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Testing Autism Drugs in Human Brain Cells

A method involving pluripotent stem cells could lead to personalized treatment of the disease.
November 11, 2010

Autism is a highly complex disorder affecting one in every 110 children born in the United States. The disease’s genetic profile and behavioral symptoms fluctuate widely from case to case, and this variability has frustrated scientists’ efforts to identify effective treatments. A new study suggests that autism could eventually be a target for personalized treatment, targeted to a patient’s own neurons.

Point of contact: This image shows two compact masses of neuron precursor cells, derived from human pluripotent stem cells. Differentiated neurons, whose nuclei are shown in red, have begun to extend neuronal processes, shown in green, toward one another, forming neuronal connections.

A team from the University of California, San Diego, and the Salk Institute for Biological Studies devised a way to study brain cells from patients with autism, and found a way reverse cellular abnormalities in neurons that have been associated with autism.

The researchers took skin biopsies from patients with a severe form of autism called Rett syndrome, and genetically reprogrammed those cells into pluripotent stem cells. Pluripotent stem cells have the power to differentiate into any kind of cell in the body, depending on environmental cues during early development. The team differentiated the stem cells into fully functioning neurons, and then studied their functioning. They found that neurons derived from patients with Rett syndrome showed certain abnormalities, including markedly smaller cell bodies, dendrite connections, and decreased cell-to-cell communication.

By treating these patient-derived neurons with an experimental drug, the researchers could reverse the cellular abnormalities. The findings, published today in the journal Cell, could give scientists a powerful tool for pinpointing the causes of autism and other brain disorders, and a way to choose targeted treatments.

“It took us two years to finish this project, and personalized medicine might not be that far off,” says Carol Marchetto, first author of the paper and a postdoctoral researcher at the Salk Institute. “In the lifetime of a patient, you could go from his skin sample to a reprogrammed cell, to differentiating into a neuron, and find drugs that could be used on that patient.”

Rett syndrome, which mostly affects girls, can cause highly impaired social and communication skills, which become apparent soon after a child learns to walk and talk. Patients with Rett can experience increased difficulty breathing and controlling their movements, and can develop repetitive and compulsive behaviors similar to other forms of autism.

Marchetto sees Rett syndrome as a gateway to the broader study of autism, since many other forms of autism share behavioral and genetic similarities with Rett syndrome.

Most cases of autism seem to stem from a combination of genetic abnormalities, but Rett arises from a single gene mutation, found on the MeCP2 gene on the X chromosome. In girls, one of two X chromosomes carries the mutation, and during fetal brain development, one chromosome is activated within each brain cell, seemingly at random. Rett patients can exhibit varying percentages of brain cells carrying the mutation, which can manifest as varying levels of severity of the disorder.

To understand how this genetic mutation plays out at a cellular level, Marchetto and her colleague Alysson Muotri, an assistant professor in the department of Molecular and Cellular Medicine at the UCSD’s School of Medicine, took skin biopsies from four patients with Rett syndrome, reprogrammed them into pluripotent stem cells and experimented with a number of different conditions before they found a combination of growth factors that differentiated the stem cells into functioning human neurons.

They saw that each patient-derived stem-cell line generated a different percentage of neurons carrying the gene mutation. The defective neurons looked and acted differently from their normal counterparts, exhibiting smaller cell bodies, less dendrite connections, and impaired cell-to-cell communication.

The researchers treated neuron cultures with insulin-like growth factor (iGF1), which has been shown to reverse behavioral symptoms of Rett in mice. The drug reversed the biological symptoms of the disorder in the neurons, restoring dendrite connections and cell-to-cell signaling in defective neurons. The researchers plan to use the same process to generate neurons from more patients with both Rett syndrome and other forms of autism.

Jeffrey Neul, assistant professor of molecular and human genetics at Baylor College of Medicine, who studies Rett syndrome in mice, says animal models allow scientists to observe the behavioral effects of the disease, but this is a time- and labor-intensive process.

“The field really has been in desperate need of cellular-based assays that can be used to test therapeutic compounds,” says Neul. “And it’s really hard to push drug discovery if you don’t have something you can do in a more rapid fashion.”

The process Marchetto and Muotri have developed takes three months to generate fully functioning human neurons. While this is similar to the time frame of normal brain development, the researchers are looking for ways to speed the process up so they can rapidly generate brain cells and expose them to a variety of molecular factors and drug compounds.

The team also plans to move beyond the Petri dish once they’ve differentiated neurons from human skin cells, to see how the neurons work in a living brain. “What we can do is transplant human neurons in mouse brains and generate chimeric [hybrid human-animal] models,” says Muotri. “We can then expose these animals to different environments, and see how they will affect the human neuron.”

James Ellis, professor of molecular genetics at the University of Toronto, is doing similar work in reprogramming patients’ skin cells into brain cells. He says that Muotri and Marchetto’s findings open up a new testing ground for autism and other neurological disorders. “That’s clearly what’s going to be required of autism, where different people are going to have different mutations and mechanisms, in how they ended up with that outcome,” he says.

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