Insulinlike growth factor–1 (IGF-1) is safe, effective, and significantly improves social withdrawal in children with a rare type of autism spectrum disorder (ASD) but may also have treatment implications for other ASDs, early research suggests.
Known as Phelan-McDermid syndrome (PMS), the disorder, which affects about 1200 individuals worldwide, is caused by a deficiency in the SHANK3 gene. The disorder likely accounts for only about 1% of all ASDs.
But a treatment for this rare form of autism could have relevance for the treatment of other ASDs, the study's lead author, Alexander Kolevzon, MD, clinical director, Seaver Autism Center, and associate professor of psychiatry and pediatrics, Icahn School of Medicine at Mount Sinai, New York City, told Medscape Medical News.
"Studies have already shown that IGF-1 is somewhat effective in Rett syndrome, and now it's been shown to be somewhat effective in PMS," he said. "It seems that many, many different causes of autism converge on common molecular pathways," he added.
The study, which is the first controlled treatment trial in PMS patients, was published online December 12 in Molecular Autism.
Synaptic Plasticity
In addition to evidence of the efficacy of IGF-1 in Rett syndrome, which is also an ASD-related condition caused by a gene deficiency, there is also preclinical evidence that IGF-1 reversed deficits in mouse and neuronal models of SHANKS3 deficiency.
The small study included nine children with PMS (6 girls and 3 boys) aged 5 to 15 years. At baseline, their mean Aberrant Behavior Checklist–Social Withdrawal (ABC-SW) subscale score was 16.9. Mean Repetitive Behavior Scale–Revised (RBS-R) total score was 32.1. All patients met criteria for intellectual disability.
The children were randomly assigned to receive IGF-1 or placebo for 12 weeks. They then crossed over to the opposite treatment after a 4-week washout period.
IGF-1 promotes the growth and maturation of nerve cells and "synaptic plasticity," or the ability of nerve cells to "connect and form networks," said Dr Kolevzon. It is commercially available but only to correct short stature.
In the study, the IGF-1 dose started at 0.04 mg/kg in twice-daily subcutaneous injections and could be titrated up to 0.12 mg/kg twice daily. Researchers aimed to reach the therapeutic dose as quickly as was safe and tolerated in order to allow maximum time for clinical improvement, said the authors.
Parents were taught to administer the shots and to carry out preprandial glucose monitoring. The treatment acts somewhat like insulin and can reduce blood sugar, Dr Kolevzon noted.
IGF-1 was generally well tolerated, with no serious adverse events. There were more side effects reported with the drug compared with placebo. The most common side effect was low blood sugar.
Turning Point?
When children were taking IGF-1, they showed significant improvement in measures of both social behavior and restrictive behaviors. After combining scores across treatment phases, the mean change on the ABC-SW score between baseline and week 12 for those on the drug was 8.2, compared with 1.5 for placebo (P = .040). The mean change in RBS-R score at week 12 was 2.0 for the drug and -0.8 for placebo (P = .042).
Because participants assigned to IGF-1 during the first phase had a higher baseline ABC-SW value than placebo participants in that phase, the researchers evaluated the differential effect of treatment over time in the context of order.
They determined that there was no effect of treatment order. As well, the washout period should have minimized the risk for treatment order effects, said the authors.
This new study may in some ways represent the proverbial turning point when it comes to researching autism treatments.
"Historically, in autism we have been targeting various associated symptoms like irritability and aggression and hyperactivity, and none of these really reflect true core deficits of autism," said Dr Kolevzon.
"So we tried to take a different approach; rather than target the associated symptoms, we targeted the biological deficits based on animal models and what we think may be a disease-modifying effect."
He and his colleagues are now conducting a study of the effect of IGF-1 in patients diagnosed "more broadly" with autism.
Cautious Optimism
Dr Kolevzon sees IGF-1 as a treatment to be taken on a long-term basis. "I don't think this will be the kind of thing that cures disease in the true sense, but will be similar to diabetes, where your pancreas doesn't make insulin. In this case, kids don't make enough SHANK3 protein; you give the medicine to try to correct that deficit, but if you stop giving them the medicine, the deficit returns."
A drawback to the treatment, however, is its cost. Dr Kolevzon estimated that it costs $12,000 to $15,000 for 3 months of treatment per patient.
It is not known whether it is even feasible to take IGF-1 long term. Because it is a growth factor, it could produce unwanted growth.
"It's unlikely that IGF-1 in its current form can be given for a very long time; how long it can be given safely, we don't know yet," said Dr Kolevzon.
But there could be other ways of boosting IGF-1 levels, he said.
"There may be ways of figuring out how to increase levels of IGF-1 in the brain without increasing levels of IGF-1 in the periphery. We don't want massive amounts of skeletal growth or muscle growth; that's dangerous."
Although there are still hurdles to overcome, Dr Kolevzon said he is "extremely excited" about this research strategy in terms of coming up with new medications for children with autism.
"I'm cautiously optimistic about IGF-1 in particular because even though this a very small study, as a clinician, it's clear to me that something meaningful is happening for these kids."
More Research Needed
Commenting on the study for Medscape Medical News, Susan E Levy, MD, Division of Developmental and Behavioral Pediatrics, Children's Hospital of Philadelphia, who is a researcher in the Center for Autism Research and is associate professor of pediatrics, University of Pennsylvania, had some concerns.
Her biggest issue was that outcome measures were assessed through questionnaires.
"They didn't use any direct observation of the kinds of behaviors and skills that you want to see are improving."
Another concern was the short study period. "I can't imagine that the kinds of results that they want to see, and that are significant and cogent, are the ones that present within 3 months."
Dr Levy also expects parents to start requesting IGF-1 for their autistic child. "As a clinician and researcher, I get a little nervous about this, because people take the leap; they see some evidence and then want to go ahead and start treating with some of these substances that have not been firmly investigated."
Dr Kolevzon and Dr Levy report no relevant financial relationships.
Mol Autism. Published online December 12, 2014. Full text
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Cite this: Insulinlike Growth Factor Promising for Rare Autism Type - Medscape - Feb 25, 2015.
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