Autism symptoms improved in five boys given a century-old drug for sleeping sickness, according to a new study led by University of California San Diego researchers.
The small clinical trial involved 10 boys, including five who received a placebo and did not show improvement. Those that received a single infusion of the drug, suramin, showed significantly better functioning in language, behavior and willingness to socialize. The gains lasted for several weeks, said Robert Naviaux, a UC San Diego professor who was the study's principal investigator.
The open-access study was published in the Annals of Clinical and Translational Neurology. It is online at j.mp/autismsuramin. (A detailed question and answer interview with Naviaux is available at this link, along with accounts from parents in the study about the improvement they saw in their children. Both were provided by UCSD.)
Autism spectrum disorder therapy is often based on behavioral methods, sometimes accompanied by drugs. It's considered most effective when treatment begins as early as possible. Consequently, much research is focused on developing methods of early screening for infants and toddlers likely to have autism.
But these boys were older than toddlers. The youngest was 5, the oldest 14; and the average age was 9.1 years. So if the research is confirmed, it would mean there's more brain plasticity in older autism spectrum disorder children than has been believed.
It would also mean that for the first time, a drug would be proven to treat an underlying cause of autism.
Naviaux said the results in this study, which primarily assessed safety, must be regarded as preliminary. However, he said the results warrant a larger trial. He's planning to test 40 diagnosed autism spectrum disorder children.
The research was preceded by a study that found suramin reversed ASD symptoms in mice. That study in Translational Psychiatry was designed to test a hypothesis of Naviaux's that autism, whatever the cause or trigger, results in reduced communication between brain cells. This is a cellular stress response that suramin is theorized to inhibit.
When the results were positive, he took the next step of testing the drug on children.
The animal study, and the new one, were funded through philanthropic donations. The new one has incurred a debt of about $500,000 that has yet to be paid for, Naviaux said.
To fund the planned larger study, about $2 million more in donations are needed. To learn more about the research, visit Naviaux's website at naviauxlab.ucsd.edu. A link at the top of the page provides information on donating.
Drug research is usually funded by pharmaceutical companies seeking to bring new medicines to market. But suramin, a drug introduced in 1916, is long off-patent, so that financial incentive is lacking.
The benefits of using such an old drug includes the lower cost of an off-patent drug, and that it has an extensive history of use, Naviaux said. This allows the risks to be better assessed than starting out with a drug that has never been put into people.
However, suramin can be toxic, Naviaux warned, so expert medical guidance is needed. For that reason, he recommends parents not experiment with the drug and risk harm to their children.
Constance Smith-Hicks, director of the Center for Autism and Related Disorders at Kennedy Krieger Institute in Baltimore, favorably assessed the research. She was not involved in the work.
"The authors show that suramin, a drug with antioxidant properties that targets the integrated stress response, is safe in children with ASD when given at low-doses," Smith-Hicks said by email.
"Although this was a small study, it's strong preliminary evidence suggest that suramin may be useful for the treatment of core features of ASD and extending this drug to larger scale testing is desirable," she said.
Anecdotal signs of improvement began within hours of a single intravenous dose of suramin, Naviaux said. This was later confirmed in all five boys with standard assessments, such as the Autism Diagnostic Observation Schedule 2, or ADOS-2.
Higher ADOS-2 scores indicate more autism symptoms. Those scoring 6 or lower are not on the spectrum; scores of 7 to 8 place them on the spectrum; and 9 and above indicates definite autism. Scores dropped by an average of 1.6 points in the treated group, but didn't change in the placebo group.
The boys came from the middle 80 percent of the spectrum, Naviaux said. The 10 percent lowest- and highest-functioning were not included, to make the results as representative as possible for the largest number of autism spectrum children.
Signs of improvement reported by the parents lasted as long as six weeks, Naviaux said, but were almost entirely gone by eight weeks. The exception is that motor skills learned during that window tended to persist.
"One of the 7-year-olds had been working for almost a couple of years learning to tie his shoes. And he learned to tie his shoes during this time. And even though the language and behavioral gains waned by eight weeks, he still could tie his shoes."
Also significant, he said, is that the treated children progressed in development in the way children normally do, moving from simpler activities to the more complex.
One treated boy became interested in playing hide-and-go-seek, then tag, soccer and games of catch, Naviaux said. While these stories are anecdotal, they do jibe with the believed mechanism of action of suramin in autism, and the progress formally documented in test scores.
These milestones, even though not recorded through formal scoring, are extremely meaningful to parents, said Naviaux and co-author Gail Reiner, a coauthor and nurse. Reiner is affiliated with UCSD and Rady Children's Hospital — San Diego.
It can be as simple as a child announcing to his parents, "I finished my dinner!," which one boy did.
That grammatically correct sentence, including the pronoun, carries enormous significance for parents searching for signs of progress, said Reiner, herself the mother of an autistic daughter.
The testing environment and the IV infusion process were designed to make them as easy as possible on the children and their parents, Reiner said.
The procedures were first explained to the children in a way they could relate to, with a storyboard method. The environment included items that they were familiar with, and the children were allowed to bring things they were comfortable with, such as a weighted blanket.
"As Dr. Naviaux put in the paper, children with autism have a difficult time with social communication," Reiner said. "They have restricted interests. They tend to have stereotypies or repetitive behaviors they do, and routine is super-important to them in order to minimize stress."
"So we take what we understand about how life is more comfortable to them and we use that understanding to minimize the stresses of participating in research."
Testing a theory
The research is rooted in a unifying theory Naviaux has developed over many years about cellular communication, and how it can go awry in autism.
Naviaux specializes in diseases associated with mitochondrial malfunction. Children whose mitochondria can't supply enough energy are unusually passive, and are prone to failure of energy-intensive organs.
"They come into the clinic with such severe neuromuscular weakness that they often can't walk. They're in wheelchairs," Naviaux said. "They have a decreased sensitivity to sound and touch."
Autism spectrum children display nearly the opposite behaviors, he said. They are hypersensitive to sound and touch and bright lights. When brought in for examination, they'll actively explore the room, opening up drawers and looking around.
The key molecule implicated in both disorders is ATP, adenosine triphosphate, which provides energy for metabolism inside the cell. Those with neuromuscular weakness have insufficient ATP. In autism, there's enough ATP, but it doesn't stay inside the cell where it belongs.
When ATP escapes outside the cell, it triggers a damage response, which causes the cells to hunker down for survival, inhibiting their ability to communicate, and causing inflammation.
"The overall idea is that autism can be caused by either genes or environment working together … that leaves the cell in a state that is primed for cellular defense," Naviaux said.
"When cellular resources are allocated for cellular defense, they're not available for normal child development."
With that hypothesis in hand, Naviaux searched for a way to restore normal cellular communication.
"I went looking through the world's pharmacopeia to find any drug that had the ability to inhibit extracellular ATP signaling. There was one in the world that was available for human use, and that was suramin. And it just so happened that it had been developed in 1916. And I wouldn't have cared if it were developed the year before."
The research was supported by the William Wright Family Foundation, the UCSD Christini Fund, the Autism Research Institute (ARI), the Lennox Foundation, the Gupta Family and Satya Fund, the Agrawal Family, Linda Clark, the N of One Autism Research Foundation, the Rodakis Family, the It Takes Guts Foundation, the UCSD Mitochondrial Disease Research Fund, Dr. Elizabeth Mumper Cooper, and the Daniel and Kelly White Family. Funding for mass spectrometers used in the study was provided by the Jane Botsford Johnson Foundation.