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Study Opens Promising New Direction in Autism Research

March 13, 2013

Autism Speaks Trailblazer research supports new theory that blocking cell distress signals can ease autism symptoms

A newly published Autism Speaks Trailblazer study supports a novel theory about the cause and potential treatment of autism. The theory holds that a chronic “cell danger response” can interfere with brain development and function – and that blocking these danger signals might be a way to treat autism.

Using a mouse model of autism, the researchers used a chemical compound to block such cell danger signals and, in doing so, reversed signs and symptoms of autism in the animal’s brains and behavior. 

The report appears today in the open-access journal PLOS ONE. It was supported by one of the first Autism Speaks Suzanne and Bob Wright Trailblazer Awards, a grant made possible by a generous gift from Amy and Stuart Savitz and Nancy and James Molesworth.

New Theory of Cause and Treatment
The findings support a theory proposed by the study’s lead author, mitochondrial medicine specialist Robert Naviaux, M.D., Ph.D., of the University of California, San Diego.

Several years ago, Dr. Naviaux proposed that cell structures called mitochondria play a broad role in the development of autism.  Mitochondria are best known for providing cells with energy. Dr. Naviaux looked beyond energy production to study their role in signaling when a cell is damaged or diseased. Under stress, cells release mitochondrial (purinergic) chemicals that normally remain inside the cell. When they leak outside a cell, these chemicals signal danger to surrounding tissues.

“In essence, these signals warn other cells to harden their defenses,” Dr. Naviaux explains. "This helps protect against cell-to-cell infection. However, it may also interfere with cell-to-cell communication."

When Danger Signals Don’t Stop
Normally, cells stop releasing their danger signals when an infection or other stress resolves. According to Dr. Naviaux’s theory, autism can result when a stress during early brain development triggers a chronic danger response. The stress that starts this chain of events can come from an environmental influence, a genetic problem or a combination of both, he proposes. The result is chronic brain inflammation and frayed connections between brain cells.  

“When the brain cells stop talking, so do children,” he says. In developing his theory, Dr. Naviaux proposed that it might be possible to reverse autism by blocking chronic cell danger signaling.

An Award to Transform Autism Research
In 2010, Autism Speaks created the Suzanne and Bob Wright Trailblazer Award Program to fund highly novel “out of the box” studies that open new avenues into understanding the prevention, causes and treatment of autism. The grant supports “high-risk/high-impact” projects with the potential to transform the field of autism research.

In the same year, Autism Speaks awarded Dr. Naviaux one of its first Trailblazer grants to test this “cell danger response” theory of autism. His team began their research by producing litters of mice that exhibited autism symptoms. They did so by mimicking a viral infection in mice during pregnancy. This “maternal immune activation mouse model” is well-known for producing mouse offspring with symptoms of autism.

The researchers measured social behavior by giving the mice opportunities to spend time with either another mouse or a Lego block in adjacent wire chambers. They also tested motor coordination as the mice walked along a rotating rod. While female pups showed only mild impairments, the male pups showed a 50 percent reduction in socializing and a 28 percent reduction in motor coordination. The researchers then used the male pups for testing response to treatment.

Compound Reverses Autism Behaviors in Mice
When the mice were 6 weeks old (roughly adolescents), 84 received an injection of suramin, a chemical that blocks mitochondrial signals leaking out of cells. For comparison, another 84 mice received a dummy shot of saltwater

The treatment restored normal socializing and motor coordination in the mice that received it. By contrast, the researchers saw no such improvement in the mice injected with saltwater.

Later, the researchers examined the mice’s brain tissue. There, they looked for the brain abnormalities associated with autism. These included abnormal cell connections (synapses) and high rates of cell death in an important class of neurons called Purkinje cells. They found elevated levels of all these abnormalities in the untreated mice. But they did not see them in the mice treated with suramin.

Guiding the Search for Safe Treatments 
In people, suramin can be used safely only for short periods because it has potentially serious side effects.

“Our hope was to test this compound first in mice, then in a small clinical trial that will use just a single dose to determine whether this class of drugs is a good direction for developing safe and effective treatments,” Dr. Naviaux says.

“Breakthroughs in the development of new treatment approaches for autism are going emerge from innovative theories and trailblazing research like that of Naviaux’s team,” says Autism Speaks Vice President for Translational Research Robert Ring, Ph.D. “Although these findings still need to be expanded and confirmed before they make their way into the clinic, this line of work emphasizes how Autism Speaks will leave no stone unturned in our search for ways to convert science innovation into applications that transform outcomes for individuals with autism.”

Autism Speaks Participant’s Guide to Autism Drug Research provides important information for families considering entry into a clinical trial of an experimental medicine. It can be downloaded at no charge here.

To read about more Autism Speaks Trailblazer studies, click here. Autism Speaks continues to fund a wealth of research on the causes, prevention and treatment of autism. You can explore all of these studies by topic using this website’s Grant Search.