An impressive new paper is just out from Robert Naviaux, Susan Powell and colleagues at UC San Diego. They use our mouse model of the autism and schizophrenia risk factor, maternal immune activation during pregnancy, to show that a drug that blocks purinergic receptors, suramin, is able to correct a wide variety of abnormalities found in human autism. A key finding is that this treatment works in mature, 6 week-old mice – that is, the treatment does not have to be initiated during early development. “Purinergic” is a term for nucleotides such as ATP, and receptors for ATP are found on the surfaces of cells throughout the body. Moreover, ATP is a transmitter used at many different types of synapses in the brain. Tying this into the theme of this blog are many observations that ATP signaling modulates immune responses and chronic inflammation, as well as anti-viral signaling, microglial activation, gut motility and permeability, and sensitivity to food allergens. Suramin inhibits purinergic signaling and has been used for treating African Sleeping Sickness (Trypanosomiasis) since the early 1900s. Treating the offspring of maternal immune activated mice weekly with suramin normalizes their social behavior, motor coordination, body temperature, mitochondrial respiratory function and other metabolic measures. Most impressively, this treatment also corrects a neuropathology that we found in this model, and which is also common in human autism.
The authors interpret their findings to suggest that there is too much purinergic signaling in the offspring of immune-activated mothers, which could lead to widespread metabolic disorders of the types seen in autism. What has not yet been shown, however, is whether human autism does, in fact, involve elevated purinergic signaling. One would also like to have seen what this treatment does to the other core autism symptoms found in this model: deficits in communication, and increased repetitive behaviors.
The striking improvements induced by weekly injections of suramin raise the question of whether this treatment could be tested immediately in autism subjects. After all, it has been used in humans for another purpose for decades. However, Naviaux has issued this declaration in response to that question: “Suramin is not suitable for long-term treatment of children with autism because of the potential for toxicity. This was included as an important caveat in the original PLOS One publication. Dr. Naviaux’s clinical trial will be a single-dose drug trial that is designed to test the general principle of antipurinergic therapy (APT) in autism. If successful, the trial may point the way to the development of newer and safer drugs. Neither Dr. Naviaux, the University of California, the Autism Research Institute, nor Autism Speaks endorses the use of suramin as a general treatment for children with autism.”
Not only for drug development, this important study highlights purinergic pathways as a key area for further study in autism pathophysiology.