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Gene tinkering curbs autism symptoms in mice

/ Source: Special to MSNBC

Scientists could be on the verge of a new treatment for autism, if the results of animal research hold up in people. A study in mice suggests that several drugs, including one that is poised to enter trials in human patients as soon as next year, could improve brain function and reverse the symptoms of some autistic patients.

So far, the research indicates the drugs will only be effective for one form of autism that is caused by a mutation of a gene on the X chromosome, a condition known as fragile X syndrome. But the researchers think there's a possibility the medications could also work for other cases of autism where the cause is unknown.

“I really hope that we can go beyond fragile X and see significant improvement in children with other types of autism,” said Mark Bear, a neuroscientist at the Massachusetts Institute of Technology who led the mice research.

Autism disorders strike 1 out of every 150 children. Currently there is no cure for autism, a complex developmental disorder that impairs a person’s ability to communicate and relate with others and is associated with a range of unusual repetitive behaviors, such as obsessively arranging objects.

The exact cause of the disorder remains elusive but it has been linked to a variety of genes, including the fragile X mutation that can lead to both mental retardation and autism. Most patients with fragile X will show some autism symptoms and about 20 percent will meet the criteria to be considered autistic. The mutation is thought to lead to mental problems because it causes hyperactivity of a brain protein called metabotropic glutamate receptor 5 (mGluR5) that normally plays a role in learning and memory.

A team led by Bear wondered if reducing levels of mGluR5 protein could restore normal brain function. The researchers used a combination of genetic engineering and selective breeding to produce a line of mice that had both the fragile X mutation and toned down levels of the mGluR5 protein in their brain. The intent was to get an idea of what would happen when the protein was suppressed using a drug in human patients.

In a finding that the researchers described as “remarkable” in Thursday’s issue of the scientific journal Neuron, the mice — which should have had mental retardation and autism-like symptoms due to the fragile X mutation — instead showed near-normal brain function and memory.

Pill in the works

That was exciting in and of itself, because it indicated that blocking the mGluR5 protein could lead to improvements in some forms of autism and mental retardation. But Bear said the even more provocative implication is that a compound that does just that already exists. A few years ago, he founded Seaside Therapeutics, a small pharmaceutical firm in Cambridge, Mass., that is developing a mGluR5-blocking drug called STX107. The agent, which would be taken as a pill, has passed all the safety studies required for beginning studies in people.

Randall Carpenter, Seaside's president and chief executive officer, said he's “cautiously optimistic,” about STX107's potential to reverse autism symptoms in people. “These are really exciting findings, but we really don't know how helpful it's going to be until we test it in humans,” he said.

Seaside now plans to meet with the Food and Drug Administration to request approval to begin clinical trials involving people with fragile X syndrome and autism. Carpenter anticipates starting the initial human studies sometime next year. 

Outside researchers also were enthusiastic about the potential of the compound.

“It seems very promising indeed,” said Matthew Belmonte, a neuroscientist at Cornell University's Department of Human Development. He said the study in mice suggests that drugs that suppress mGluR5 can restore brain function without causing any other ill effects. That bodes well for human trials, Belmonte said, but he noted that suppressing a gene in an animal study is not the same as using a drug in people so there could be unforeseen risks that may turn up.   


Not everyone is on board, however. Sophia Colamarino, a neurobiologist and vice president of research for the advocacy group Autism Speaks, which helped fund Bear's research, said the finding “give us hope” that this could be a viable strategy for treating autism, but she added that it's too early to tell whether STX107 will improve autistic behaviors in people. The drug could reduce mGluR5 levels, but autism is such a complex disease, this may not be enough to restore normal behavior in patients, Colamarino said.

Two other drugs in the works

If the drug does fail, there still may be hope for patients and their families. The Fragile X Research Foundation (FRAXA), which co-funded STX107 research, is supporting investigations involving two other drugs that block the same protein.

Lithium, which is used for treating depression and bipolar disorder, is being investigated for its potential to treat autism and fragile X by researchers at Rush University in Chicago.

And another compound called fenobam — initially developed as an anti-anxiety medication in the 1970s and then abandoned — is being revitalized for fragile X by Neuropharm, a Surrey, UK-based pharmaceutical company.


“We believe that drugs which block mGluR5 have enormous potential for the treatment of fragile X and related developmental disorders, including many cases of autism,” said Katie Clapp, president and executive director of FRAXA.

Steve Mitchell is a science and medicine writer in Washington, D.C.  His articles have appeared in a variety of newspapers, magazines and Web sites, including UPI, Reuters Health, The Scientist and WebMD.