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GEN News Highlights : Mar 14, 2013
Hope for Autism Lies in Century-Old Drug
Testing a new theory, researchers have used a newly discovered function of an old drug to restore cell communications in a mouse model of autism, reversing symptoms of the disorder.
“Our cell danger theory suggests that autism happens because cells get stuck in a defensive metabolic mode and fail to talk to each other normally, which can interfere with brain development and function,” says Robert Naviaux, M.D., Ph.D., professor of medicine and co-director of the Mitochondrial and Metabolic Disease Center at the University of California, San Diego School of Medicine. “We used a class of drugs that has been around for almost a century to treat other diseases to block the ‘danger’ signal in a mouse model, allowing cells to return to normal metabolism and restore cell communication.”
Nearly a dozen UC San Diego scientists from different disciplines collaborated to find a unifying mechanism that explains autism. Describing a completely new theory for the origin and treatment of autism using antipurinergic therapy (APT), Dr. Naviaux and colleagues introduce the concept that a large majority of both genetic and environmental causes for autism act by producing a sustained cell danger response—the metabolic state underlying innate immunity and inflammation.
“When cells are exposed to classical forms of dangers, such as a virus, infection, or toxic environmental substance, a defense mechanism is activated,” Dr. Naviaux explained. “This results in changes to metabolism and gene expression, and reduces the communication between neighboring cells. Simply put, when cells stop talking to each other, children stop talking.”
Since mitochondria play a central role in both infectious and noninfectious cellular stress, innate immunity, and inflammation, Dr. Naviaux and colleagues searched for a signaling system in the body that was both linked to mitochondria and critical for innate immunity. They found it in extracellular nucleotides like adenosine triphosphate (ATP) and other mitokines—signaling molecules made by distressed mitochondria.
These mitokines have separate metabolic functions outside of the cell where they bind to and regulate receptors present on every cell of the body. Fifteen types of purinergic receptors are known to be stimulated by these extracellular nucleotides, and the receptors are known to control a broad range of biological characteristics with relevance to autism.
The researchers tested suramin—a well-known inhibitor of purinergic signaling used medically for the treatment of African sleeping sickness since shortly after it was synthesized in 1916—in mice. They found that this APT mediator corrected autism-like symptoms in the animal model, even if the treatment was started well after the onset of symptoms.
The drug restored 16 types of multisymptom abnormalities including normalizing brain synapse structure, cell-to-cell signaling, social behavior, motor coordination, and normalizing mitochondrial metabolism. More specifically, the drug prevented cerebellar Purkinje cell loss, correction of the ultrastructural synaptic dysmorphology, and correction of the hypothermia, metabolic, mitochondrial, P2Y2 and P2X7 purinergic receptor expression, and ERK1/2 and CAMKII signal transduction abnormalities.
“The striking effectiveness shown in this study using APT to ‘reprogram’ the cell danger response and reduce inflammation showcases an opportunity to develop a completely new class of anti-inflammatory drugs to treat autism and several other disorders,” Dr. Naviaux says.
“Of course, correcting abnormalities in a mouse is a long way from a cure for humans,” he adds, “but we are encouraged enough to test this approach in a small clinical trial of children with autism spectrum disorder in the coming year. This trial is still in the early stages of development. We think this approach offers a fresh and exciting new path that could lead to development of a new class of drugs to treat autism.”
The findings are published in the March 13 issue of PLOS ONE in an article titled “Antipurinergic Therapy Corrects the Autism-Like Features in the Poly(IC) Mouse Model.”
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