Dr. Robert Naviaux, MD, PhD, Physician-Scientist and Professor of Genetics in the Departments of Medicine, Pediatrics and Pathology at UC San Diego School of Medicine talks about a drug that used to be used for African sleeping sickness, and is now being tested to help children with Autism.
Interview conducted by Ivanhoe Broadcast News in March 2018.
Let’s talk about suramin; it’s kind of amazing that you found it. Why were you looking for it and how did you find it?
Dr. Naviaux: All of our work traces back to our original interest in the power plants of the cell called mitochondria, and specifically in genetic forms of mitochondrial disease. The path to suramin is one that involves over a dozen different threads or streams that come to a confluence at autism. We had to make a number of intermediate discoveries along the way first. First we had to understand that mitochondria were not only the power plants but they are also battleships in the cell that help defend the cell against external threat, infection and injury. We defined something called the cell danger response, the CDR, that is a universal cellular response to any kind of threat or infection. The CDR gets activated and when a virus enters a cell or a toxin or even when there’s physical injury. That sets up a sequence of metabolic changes that creates a syndrome, a metabolic syndrome. Ultimately we discovered that children with autism have a persistent activation of this cell danger response. These metabolic pathway abnormalities cause cells to do what nations do when they go to war, and that is they harden their borders and don’t trust their neighbors. Then they change how they communicate with their neighbors. One way of thinking about it is when cells stop talking children stop talking. That was a start and then we learned that one of the fundamental regulators of the cell danger response was a molecule called ATP. ATP inside the cell is an energy carrying molecule, but ATP outside the cell is a damage and danger signal. And it binds to over a dozen different receptors that are widely distributed in the body to help change cellular metabolism to allow the cell to defend itself. We reasoned that if children had this activated cell danger response that was maintained by too much extracellular ATP that a drug that could compete with extracellular ATP might help to rebalance the cell danger response and restore normal development. Back in 2008 I went looking through the world’s pharmacopoeia over two thousand different drugs to find any drug that could inhibit extracellular ATP signaling. There was exactly one drug and that was already available for clinical use and that was suramin.
What was it used for and how old are we talking?
Dr. Naviaux: It was used for treating African sleeping sickness and was developed in 1916.
Which didn’t exactly make it easy to find.
Dr. Naviaux: For the past fifty years the manufacturer of suramin has been making a few kilograms of it and providing it to the World Health Organization in Geneva to be distributed in Africa to treat African sleeping sickness. It just has not been on the economic ledger for that company for a long time. But it is still on the World Health Organization’s list of essential medications to this day.
You find out that suramin might work, then what happens?
Dr. Naviaux: A way of testing this is in an animal model of autism. We ultimately conducted three different animal studies. One in a model designed to produce autism-like symptoms, behaviors and learning disabilities by an environmental trigger. That’s called the maternal immune activation, or MIA model where you simulated a viral infection during pregnancy, producing symptoms in the mom only for a day, but in the offspring produces lifelong abnormalities and behavioral and learning disabilities, and activated inflammatory cells in the brain that last for life. We also tested suramin in a genetic model of autism caused by the fragile X mutation. We found that in both the MIA and Fragile X models, suramin corrected all of the behavioral and learning disabilities if you started treatment in the first month of life. We did another study were we looked at animals with autism symptoms that were the age equivalent of a thirty year old that had never been treated before. And even in that animal the behavioral symptoms and social abnormalities were completely corrected. Although we were unable to correct a gait coordination abnormality that occurs. So some children with autism will have a little bit of a coordination problem with their gait. That’s something that we were not able to correct with the suramin. But the behavior and learning disabilities melted away.
So you move on to testing kids?
Dr. Naviaux: Yes, children.
Tell me a little bit about that.
Dr. Naviaux: Sure. We developed what we wanted to be a Phase I/II clinical trial of ten children. Ten children with autism five to fourteen years of age, all boys, half of them received suramin and half received a placebo. Part way through the trial we began noticing very significant difference in half the kids. It was blinded to us. We took pains to make sure that the clinicians that took care of the children in the clinic were separate from the behavioral therapists that were scoring the behaviors. Children began to talk, sometimes for the first time in sentences in their life. Ultimately at the conclusion of the study we found that the average child had been able to reduce their autism severity score by about 20%, from eight point six (8.6) to seven (7.0), and by definition a score of seven to ten is autism spectrum. If the average had gotten down below seven then some children would come off the autism spectrum.
You did one dose, so was it lasting?
Dr. Naviaux: The half-life of suramin after one dose is about two weeks. After several doses the half-life can extend to four to six weeks. What we found is that we had not designed the study to optimally capture the maximum time of benefit. We had timed our observations and testing of behaviors at two days and six weeks after the infusion and we had believed that six weeks would be a time when everybody had just returned to normal after the drug had washed out. And what we learned was quite the contrary; half of the children still had significant improvements in all the core symptoms of autism. Social behaviors, language and repetitive movements were all improved. In addition to a number of other things that are not core symptoms but are frequently considered as challenging comorbid conditions. Such as picky eating, fragmented sleep, difficulty with developmental milestones in school, and fine motor skills. After eight weeks, all the children had returned to normal with regard to their language and social interactions. But some children had learned to tie their shoes for the first time, or to zip up a jacket. Those fine motor skills were motor memory that had been retained. Whereas the language, cognitive and behavioral changes went back to their baseline before treatment.
This has amazing potential for families for somebody with autism, right?
Dr. Naviaux: We absolutely believe that this could be a way for some children to experience dramatic improvements. One of the things that the next clinical trials are designed to determine is whether suramin is safe and effective when given as three doses over three months. If the results are positive in a compelling number of children, in a rigorously designed clinical trial, then a set of three to four additional studies, culminating in a multicenter Phase III clinical trial, will be conducted. All these studies might take anywhere from three to five years to complete.
Can we do that one more time in a shorter version?
Dr. Naviaux: Sure. We believe that suramin is just the first in a new class of medicines that work in a similar way by inhibiting extracellular ATP signaling. The next trials that will be directed at determining if it is safe and effective in treating autism. After that, there will be a series of new clinical trials culminating in a Phase III multicenter trial that could be conducted within the next three to five years.
It’s pretty exciting because there’s not really anything for these kids right now and these families.
Dr. Naviaux: That’s right. There’s no FDA approved drug for the treatment of the core symptoms of autism. And that’s something that has really been a frustration to many families around the world.
So this is a gigantic step?
Dr. Naviaux: It could be. We’re very excited. If this is a path forward then the success of the next clinical trials will stimulate new research that will develop new drugs that work like suramin, and pretty soon instead of having one drug, we’ll have a shelf-full of drugs that doctors can pick and choose and match the needs of individual children.
What haven’t I asked you that you want to make sure that we put in this story?
Dr. Naviaux: I think that we’ve covered a lot of it. The important thing to remember is just that medicine progresses by the intellectual framework we use for understanding disease. And when there’s a shift in how we understand disease it can produce a complete change in how we think about potential treatments for those disorders. It’s exciting that contrary to what physicians are taught in medical school that autism is a permanent disorder, there may be aspects of it that are the result of a metabolic syndrome that can be treated.
END OF INTERVIEW
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