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Drug Trials for Autism

Treatments are being tested for three inherited forms.
December 3, 2008

Three drugs will be tested in humans to treat rare, inherited conditions that are often linked to autism: Rett syndrome, fragile X, and tuberous sclerosis complex (TSC). Scientists hope that the new drugs, if successful in the current trials, will eventually help treat more common forms of autism, which affects about 1 in 166 children in the United States. Existing drugs are used to treat symptoms of autism, such as digestive problems and psychosis, rather than the root of the disease.

Improving autism: Scientists will soon test IGF (insulin-like growth factor), shown here, to find out if it can reverse symptoms of Rett syndrome, a rare inherited disorder linked to autism.

“We may have our finger on a biochemical pathway that is applicable more generally in autism,” said Mark Bear, a neuroscientist at MIT, at the Autism Consortium annual symposium in Boston last month.

One of the most puzzling problems with autism is that the brains of affected children look normal, making it difficult to know where to target new treatments. The discovery in the 1990s of the mutations underlying the three disorders has allowed scientists to create animal models with the same genetic mistakes. These animal models have enabled the search for more subtle molecular processes gone awry in each disease, such as abnormal gene or protein expression that changes the electrical properties of neurons, or the architecture of the synapse–that is, the connections between neurons.

In the past year, several groups have published novel treatments that appear to reverse the damage done in these diseases. “We had thought that in disorders like autism and fragile X, damage was done early, and the best we could do was stop it,” said Story Landis, director of the National Institute for Neurological Disorders and Stroke, at the Society for Neuroscience conference, in Washington, DC, last month. But these studies show that you can intervene early and perhaps restore cognitive function, she said. Findings from these studies are now being tested in humans.

People with fragile X, the most common form of heritable mental retardation and a leading cause of autism, have a mutation in the FMRP gene, which normally inhibits protein synthesis stimulated by a receptor called metabotropic glutamate receptor 5, or mGluR5.

Last year, Bear and Gul Dolen, also at MIT, announced that they could correct abnormal brain development and faulty memory and reduce seizures in affected mice by decreasing mGluR5 activity by 50 percent. “The idea that you could reintroduce function is a sea-change event,” said Emanuel DiCicco-Bloom, a neuroscientist and physician at the University of Medicine and Dentistry of New Jersey, at the neuroscience conference.

Experimental drugs that target the receptor are already under development, although none have yet been approved by the Food and Drug Administration. Human trials of one such drug is now under way, sponsored by Seaside Therapeutics, a company founded by Bear.

TSC, another genetic disorder linked to autism, is caused by mutations in one of two genes, which trigger development of benign tumors in the brain, eyes, heart, kidney, skin, and lungs. About 90 percent of TSC patients have epilepsy, and 50 percent have autism or other cognitive impairments.

The normal function of the TSC genes is to turn off a protein called mTOR, a potent cell-growth stimulator. Animal research shows that rapamycin–an immunosuppressant drug that turns off mTOR–can reduce seizures and abnormal brain enlargement in affected animals, as well as improve learning and memory.

Previous small-scale studies of rapamycin in patients with TSC have shown that it can reduce the size of tumors, but those studies did not look at the drug’s affect on seizures and cognitive symptoms. Mustafa Sahin, a neurologist and scientist at Children’s Hospital Boston, is now planning a randomized trial of rapamycin in 55 patients ages 6 to 21. Scientists will specifically assess seizures, cognitive function, and other symptoms of autism.

Migranka Sur, a neuroscientist at MIT, hypothesizes that synapses in people with Rett syndrome, a disorder characterized by seizures, mental retardation, and motor problems, remain immature but can be chemically induced to mature. “IGF [insulin-like growth factor] and EGF [epidermal growth factor] are two pathways we think can be activated to make synapses mature,” Sur said at the autism symposium. His group recently showed that treating mice with the Rett mutation with a fragment of the IGF protein stimulated synapses, improved motor function, and extended life span.

Scientists in Sur’s lab are now planning a placebo-controlled clinical trial of IGF in girls ages 2 to 10. The drug is already approved to treat children with short stature, so its safety profile is well known.

Scientists are particularly excited about the new drug trials because they target specific molecular processes believed to be at the root of these diseases. “These are not palliative approaches,” said Bear at the autism conference.

While initial trials will focus on these three specific diseases, Bear and others hope that the treatments will prove more broadly applicable. “The hope is that we’ll uncover pathways that are involved in cases of autism with unknown etiology,” said Bear. Even though there may be hundreds of genes affected in different cases of autism, he said, “I strongly suspect that there will be a few key pathways, so drugs that regulate that pathway may have a broad impact.”

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