A century-old therapy for African sleeping sickness has been used in a new study to reverse symptoms of autism in a mouse model.
The study, conducted by researchers at the University of California-San Diego (UCSD) School of Medicine and published in Translational Psychiatry, expands on the theory that autism is caused by a variety of interconnected factors.
"Twenty percent of the known factors associated with autism are genetic, but most are not," explains senior author Dr. Robert K. Naviaux, professor of medicine, pediatrics and pathology and co-director of the Mitochondrial and Metabolic Disease Center at UCSD.
Dr. Naviaux says it is wrong to think of genes and the environment as separate factors. "Genes and environmental factors interact," he stresses. "The net result of this interaction is metabolism."
Metabolic disturbances are known to be a universal symptom of autism.
"Cells have a halo of metabolites and nucleotides surrounding them," explains Dr. Naviaux. "These create a sort of chemical glow that broadcasts the state of health of the cell."
When cells are threatened or damaged by viruses, bacteria or chemicals, they react defensively by stiffening their membranes, altering metabolic processes and reducing communication with other cells.
Known as the "cell danger response," these defensive tactics can result in permanent damage if the response persists, including delayed neurodevelopment in children.
Dr. Naviaux likens the cell danger response to a wartime scenario:
"Cells behave like countries at war. When a threat begins, they harden their borders. They don't trust their neighbors. But without constant communication with the outside, cells begin to function differently. In the case of neurons, it might be by making fewer or too many connections. One way to look at this related to autism is this: when cells stop talking to each other, children stop talking."
Investigating the cellular signaling system involved in this process, Dr. Naviaux and his team focused on the role of nucleotides, such as adenosine triphosphate (ATP), and the receptors linked to autism - known as "purinergic receptors" - to which these nucleotide molecules bind.
Sleeping sickness drug inhibits signaling pathway implicated in autism
In the new study, the team wanted to see if they could inhibit this purinergic signaling using a drug. The drug they used in this trial was suramin - a treatment for African sleeping sickness (trypanosomiasis) that was synthesized in 1916.
The "cell danger response" can result in permanent damage if the response persists, including delaying neurodevelopment in children.
In mice engineered to have symptoms of autism spectrum disorder (ASD) - who were the human biological age equivalent of 30 years old - the researchers found that suramin successfully blocked the ATP signaling pathway, which halted the cell danger response.
Once the danger response ended, the cells and metabolism in the mice began behaving normally. The researchers then observed that the mice's autism-like behaviors were corrected.
Although this progress is encouraging, there are some drawbacks to suramin as a treatment. Though beneficial, the effects of the drug are not permanent or preventive, as a single dose of the drug was only effective in the mice for about 5 weeks.
Also, suramin cannot be used as a long-term treatment as it is associated with severe side effects, including anemia and adrenal gland dysfunction.
Despite this, a small phase 1 clinical trial is due to be launched later this year, assessing the treatment in children with ASD.
Dr. Naviaux suggests that the treatment, rather than being used as an autism "cure," may be used effectively to complement non-drug behavioral and developmental therapies.
"The discovery that a single dose of medicine can fundamentally reset metabolism for weeks means that newer and safer drugs might not need to be given chronically," he adds.
Dr. Naviaux explains that a new class of medicines operating along these lines may only need to be given intermittently, "during sensitive developmental windows." He concludes:
"Obviously correcting abnormalities in a mouse is a long way from a cure in humans, but we think this approach - antipurinergic therapy - is a new and fresh way to think about and address the challenge of autism.
Our work doesn't contradict what others have discovered or done. It's another perspective."