Mighty molecule: Insulin growth factor, which is used to treat a form of dwarfism, is also showing promise for certain autism-related disorders.

Insulin-like growth factor (IGF-1) improves social behavior and lessens repetitive behaviors in children with Phelan-McDermid syndrome, according to the results from a preliminary clinical trial. Researchers presented the data yesterday at a satellite meeting of the 2014 Society for Neuroscience annual meeting in Washington, D.C.

IGF-1 is also in clinical trials for treating Rett and fragile X syndromes, two other autism-related disorders. Last week, a separate set of researchers announced that the drug appears to be safe and effective in a trial of 53 adolescents and adults with Rett syndrome.

Phelan-McDermid syndrome is caused by deletions that encompass SHANK3, a top autism candidate gene. People with the syndrome have intellectual disability, muscle weakness, frequent seizures and usually autism.

About 1 percent of people with autism have small mutations in SHANK3. Because of this, the treatment may help people with various forms of autism, the researchers say.

“It’s very promising; I’m very optimistic,” says Katy Phelan, director of the cytogenetics laboratory at Tulane University School of Medicine in New Orleans, who is not involved in the trial. Phelan identified the first case of the syndrome in 1992.

At the meeting, Alexander Kolevzon, clinical director of the Seaver Autism Center in New York City, showed home videos of a girl with Phelan-McDermid syndrome as she neared the end of the trial. A roomful of researchers, 11 parents, a child with the syndrome and his brother all watched as she ate her first ice cream cone and rode on a scooter for the first time.

This sort of improvement is “meaningful and it’s overwhelming,” says Kolevzon. However, he is careful to note that the results are preliminary. “It’s a tiny trial, nine kids so far, and we could have just gotten lucky. The intent is not to say that this is the next panacea.”

Valuable investment:

The rationale for using IGF-1 is based both on animal studies and on positive results from the trials underway for other disorders. IGF-1 fixes problems with cell-to-cell communication in mice lacking SHANK3, and in neurons made from the skin cells of people with the disorder.

The Rett trial uses a modified form of IGF-1 that includes only the first three amino acids, but which may induce production of the full-length form in the brain. The Phelan-McDermid trial uses the full molecule, approved by the Food and Drug Administration (FDA) for dwarfism.

“It’s a tiny trial, nine kids so far, and we could have just gotten lucky. The intent is not to say that this is the next panacea.”

The pilot trial, with nine children, cost $14,000 per child for the duration of the study. The researchers are in negotiations with AMGEN, the company that manufactures the drug, to try to get it for free. The researchers have enrolled 45 people so far, and the National Institutes of Health has agreed to fund testing for 18 children.

“We knew that the only way to have anybody consider doing something larger was to have a small trial that shows some evidence of efficacy that was believable,” says Joseph Buxbaum, director of the Seaver Autism Center, who led the trial. “We did what we said we were going to do.”

The trial used a crossover design: About half of the children got the drug for 12 weeks, while the other half received a placebo. Four weeks later they switched. Children taking the drug were significantly less withdrawn in social interactions, which was the primary measure of success, and showed fewer repetitive behaviors.

This choice of outcome measure is crucial, as the trial’s success depends on it. In this case, the researchers used a questionnaire called the Aberrant Behavior Checklist (ABC) to evaluate social interactions. The ABC is a parent report, and is a quantitative measure of a qualitative behavior, says Walter Kaufmann, director of the Rett Syndrome Program at Boston Children’s Hospital. Kaufmann is conducting his own clinical trial of IGF-1 for Rett syndrome and served as a consultant on the Phelan-McDermid trial.

“I don’t love the ABC,” he says. “We use it ourselves, but we know the limitations.”

The researchers are developing more quantitative measures of improvement, such as brain imaging, electronic sensors that measure gait, and computer software that detects subtle improvements in language, called LENA. At the meeting, Kolevzon showed a computer avatar that captured the gait of one of the girls in the study, which was generated from 16 electrodes placed on her body. However, the FDA does not recognize any of these objective measures as relevant for autism.

The drug has some side effects, most notably low blood sugar. This may tip off parents that their child is receiving the drug, says Kolevzon. Another concern is that IGF-1 is only approved for children who are still growing — usually up to 15 years of age. Many parents are anxious about the pace of these studies because their children might not qualify for treatment by the time the drug is approved, says Phelan.

Still, taking IGF-1 later in life might be advisable if it is highly effective, says Buxbaum. “When you look at the kids who have taken IGF-1 for other syndromes, they take it for years,” he says. ”If we see efficacy, we’re going to go back to the FDA and say: We want to try it now in 20-year-olds.”

If it is safe for long-term use, IGF-1 is probably the most promising autism treatment so far, says Kolevzon. About 15 minutes after his presentation, he received an email that the study had been accepted for publication.

“Autism has been littered with decades of false promise and small pilot trials that turn out to be nothing, and even silly, silly medicines that lead to a lot of hope but go nowhere,” he says. “Having seen all these kids, I feel like there’s something meaningful happening here.”

For more reports from the 2014 Society for Neuroscience annual meeting, please click here.