Researchers alleviate symptoms of Rett syndrome in mice

Rett syndrome is a debilitating neurological disorder occurring primarily in girls. While some existing therapies might ease particular symptoms of the condition, there is no current way to address the syndrome at a molecular level. Now, researchers at Whitehead Institute for Biomedical Research, in collaboration with scientists at Brandeis University, have dramatically reduced certain manifestations of Rett Syndrome in mice, marking a clear path in which to explore possible therapies for people.

“This is the first time we’ve successfully reduced the awful symptoms of Rett syndrome using transgenic techniques,” says Whitehead Member Rudolf Jaenisch, senior author of the paper that will be published February 2 in the journal Neuron. “Once we understand the molecular mechanisms of the disease we may be able to design rational strategies that may eventually be useful for the improving the condition in people.”

Rett syndrome, whose incidence is roughly 1 in 15,000, is caused by a defective gene on the X chromosome. Most boys with Rett syndrome die before birth. Girls with Rett develop normally until about six to eighteen months, when things begin to go terribly wrong. Their health deteriorates, and they begin to show symptoms such as loss of speech, loss of voluntary motor control, constant hand wringing and seizures.

In March 2001, researchers in the Jaenisch lab published a paper in Nature Genetics describing how they had created the first mouse with Rett syndrome by disabling a gene called MeCP2. Normally, MeCP2 regulates the activities of other genes, particularly those in the brain. When it is shut off completely, the mice become lethargic and a major class of cortical neurons became far less active–classic symptoms of Rett.

In the fall of 2003, Jaenisch and researchers at Children’s Hospital Boston reported in the journal Science that MeCP2 interacted with a neuronal gene called Bdnf, a gene that’s highly active in infants age 6 to 18 months–the same age at which Rett symptoms first appear. But since this study was conducted using explanted neurons in a laboratory dish, researchers still had many unanswered questions about the role of Bdnf in Rett disease progression in mice.

Qiang Chang, a postdoctoral scientist in the Jaenisch lab, began to explore this issue by studying the population of the MeCP2 knock-out mice that Jaenisch had reported on in 2001. His first finding, gleaned through analyzing brain tissue, was not altogether unexpected: Mice without MeCP2 also showed low expression levels of the BDNF protein. In fact, Chang discovered that when he knocked out Bdnf altogether in normal mice, symptoms similar to those observed in the Rett mice occurred. But to discover whether or not these finding might have therapeutic relevance, Chang needed to engage in some complex genetic tinkering.

Chang inserted an additional Bdnf gene into the early embryos of the MeCP2 knock-out mice. He designed the gene so that it would be free of all normal regulatory mechanisms, in effect ensuring that it remains in a state of constant activity. In other words, while MeCP2 was permanently shut off, the new Bdnf was permanently switched on, and at maximum capacity.

This time, the findings were striking.

With BDNF hyper-expressed, Chang witnessed a drastic reduction in certain Rett symptoms. The mice were far less lethargic, and activity in the cortical neurons increased. These mice also had slightly larger brains, a longer lifespan and later onset of disease than the other Rett mice.

“The next step,” says Chang, “is to figure out exactly why this is happening. Exactly how much BDNF expression in the mouse brain do you need to achieve these results, and where does it occur?”

“Knowing more about the process and about the precise areas of the brain that are affected will give us options for exploring future therapies,” explains Jaenisch, who is also a professor of biology at MIT.

“We’re encouraged by these results,” says Monica Coenraads, co-founder and director of research for Rett Syndrome Research Foundation, who helped support this work. “Should this prove to be therapeutically relevant, we look forward to participating in the transition from lab to clinic.”