N of One: Autism Research Foundation Interviews Robert Naviaux, MD PhD on Suramin & Autism Trial
Robert Naviaux MD, PhD is Professor of Medicine, Pediatrics, and Pathology at the University of California, San Diego (UCSD) School of Medicine. He is the founder and co-director of the Mitochondrial and Metabolic Disease Center and former President of the Mitochondrial Medicine Society (MMS). He is an internationally known expert in human genetics, inborn errors of metabolism, metabolomics, and mitochondrial medicine. He is the discoverer of the cause of Alpers syndrome. Starting in 2008, Dr. Naviaux began investigating autism from a metabolic standpoint and soon came to view that the underlying mechanism of autism might be metabolic and regulated by the mitochondria.
In 2013 Dr. Naviaux published the first of several papers about his cell danger response theory of autism and experiments in autism mouse models where he was able to reverse both the outward behaviors and biochemical abnormalities observed. In 2015 he obtained approval to try suramin in humans.
Dr. Naviaux is a brilliant researcher with a prodigious grasp of biology. N of One has been a close collaborator since its inception. We are proud to have supported his work and commend him on his latest findings.
As part of our ongoing series to connect you with researchers describing their work in their own words we present: A conversation with Dr. Robert Naviaux about his suramin trial in humans.
In everyday language, or for people who may not have a science background, what were the main takeaways from the trial?”
Naviaux: The main conclusions from the study do not require any background knowledge. Although the study was small and preliminary, the main conclusions were three: 1) For many children, the symptoms of autism are not permanent and can be improved dramatically with the right treatment; 2) A treatable metabolic syndrome contributes to the core symptoms of autism and 3) A single treatment with low-dose suramin was safe and produced significant improvements in the core symptoms and metabolism associated with ASD.
Can you briefly describe the trial?
The first suramin trial (SAT-1) was conducted at University of California, San Diego (UCSD) School of Medicine in the Fall and Winter of 2015-16. The goals of the trial were: 1) to test the idea that the Cell Danger Response and abnormalities in purinergic signaling underlie autism and 2) to examine the safety and pharmacology of low-dose suramin in children with autism.
The trial was double-blind and placebo controlled. This means that half the participants were given suramin and the other half were given a placebo. Everybody who was involved in the trial was "blinded" meaning they did not know who was getting the placebo or the suramin, including myself.
We tested 10 male subjects ages 5-14 years. The subjects were matched into 5 pairs by age, IQ, and autism severity. At that point, one of each pair was randomly selected to receive a single intravenous dose of suramin (20mg/kg) and the other received the placebo (saline). We evaluated the children at two points in time after treatment: 2 days after their dose and then again six weeks later. We also monitored physical and neurological exams, and took samples so we could closely monitor changes to their blood and urine chemistry.
Why just a single dose?
Even though suramin has been around for 100 years, it has never been tested in a pediatric autism population before, so this was really uncharted territory. The rationale for the single dose was to err on the side of caution because high doses of suramin given for prolonged periods of time in cancer patients have been associated with significant side-effects.
Did you see any side-effects?
We did not find any serious side effects or safety concerns in this first study of a single, low-dose of suramin. We did see a self-limited, asymptomatic rash, but this disappeared without treatment in 2-4 days. Using low-dose suramin, we did not see any of the serious side effects that were seen using high doses in cancer patients
It's important to remember though that we were using a very low dose of suramin -- lower than anything that has been tested for any disease in the nearly 100 years that suramin has been used in medicine. To put this in perspective. The low-dose that we used produced blood levels of 5-15 µM. All previous uses of suramin have been at medium doses for African sleeping sickness that produced blood levels of 50-100 µM for 1-3 months, or high doses for cancer chemotherapy that produced blood levels of 150-270 µM for 3-6 months.
One caveat however about side-effects is that our study was small and only 5 boys received suramin. We were unable to detect rare side effects that might affect fewer than 20% (1 in 5) patients. Larger clinical trials will be needed to detect uncommon side effects. For example, a study in which at least 100 children received suramin would be necessary to detect a side effect that occurred in just 1 out of 100 (1%) of children.
How did you assess improvements?
We evaluated the subjects using the most commonly used tests in clinical trials. Specifically we use the ADOS (Autism Diagnostic Observation Schedule), ABC (Aberrant Behavior Checklist), ATEC (Autism Treatment Evaluation Checklist), and CGI (Clinical Global Impression questionnaire). These tests evaluate the degree of impairment in areas such as speech and language, social interaction, restricted interests and repetitive behaviors among and other behaviors and impairments commonly associated with autism.
What did you find?
A single infusion of suramin was associated with improved scores for language, social interaction, and decreased restricted or repetitive behaviors measured by ADOS, ABC, ATEC, and CGI scores at the 6 week evaluation. There were also some improvements noted after 1 week with the ABC and ATEC, but most of the improvements captured by standardized measures were found at 6 weeks. None of these improvements occurred in the 5 children who received placebo.
What did the parents report?
In the first days and weeks after the dose we began receiving reports from the parents of various improvements. In most of these cases the improvements were in biggest problem areas for the affected children. We had four non-verbal children in the study, two 6 year olds and the two 14 year olds. The parents of the 6 and 14 year olds who received suramin reported that they said their first sentence of their lives about 1 week after the single suramin infusion. This did not happen in any of the children given placebo.
The parental reports suggest that the developmental gains after suramin treatment happened in the expected sequence for normal child development, but at an accelerated rate. For example, the 2 non-verbal children first started singing nonsense tunes around the house, practicing making new sounds with their mouth and tongue and lips, like the sounds babies make before they are able to speak. In another example, the 14-year old boy who had a social developmental age of about 2.5 years, asked to play hide-and-go-seek in the first week after treatment. The following week, he began to play tag with his neurotypical brother, then soccer, then games of catch.
So did the benefits last?
The parents of the treatment group told us that improvements continued to increase for about 3 weeks after the single dose of suramin, then gradually slowed and began to decrease back toward baseline in the next 3 weeks. This timing surprised us and could not have been predicted from what was known about the pharmacology of suramin before this study. Even at 6 weeks after the single infusion, however, when the parents were reporting that the benefits were fading, there was an average of a 1.6 point improvement in the ADOS scores, from 8.6 at the start to 7.0 after 6 weeks. This is highly promising, since autism spectrum disorder (ASD) is defined has having an ADOS score of 7 to 10. If a child has a score that is lower than 7, their symptoms have decreased to the point that he or she is no longer considered to have ASD. Our hypothesis is that if we had evaluated the children earlier, we might have seen an even greater improvement. We will look to modify our methodology in the next trial. Also, in our next study we will examine what happens when multiple doses are given.
Would suramin need to be given for life?
I don’t think so, but we don’t have the science to answer this question yet. More studies will be necessary to see if improved development can become self-sustaining without the need for regular suramin treatment.
Let's talk about the biology behind all this for a moment. What is purinergic signaling?
Cells have to be able to monitor their nearby environment to monitor for potential threats. One of the ways they do this is through purinergic signaling. Purinergic comes from the word purine. A purine is a type of chemical found inside the body. The best know purine is ATP but there are many others. Inside the cell ATP is an energy carrier. Outside the cell, extracellular ATP (eATP) is a danger signal. The cell is constantly monitoring the levels of purines outside the cell, looking for danger. It does this through a variety of receptors (P1, P2X, & P2Y receptors) that bind to purines. This is purinergic signaling - the receptors are monitoring their nearby environment and signaling danger to the inside of the cell, particularly the mitochondria. I hypothesized that abnormalities in purinergic signaling were responsible for maintaining the cell danger response (CDR) as an early and fundamental problem with autism. I also hypothesized that if I could find a compound or drug that also bound to those receptors, we might be able to stop the pathological persistence of the cell danger signals and permit the cell to reallocate resources for healing and healthy function instead of cellular defense.
What led you to pick suramin?
In 2008, I searched the world for any drug that could inhibit eATP signaling. There was only one drug in the world that was known to do this and was available for use in humans. This was suramin. Suramin has many actions. One of its best-studied actions is as an inhibitor of purinergic signaling. For simplicity, we call suramin an “antipurinergic" drug because it inhibits signaling. There are many other antipurinergics under investigation for other conditions, but most are all still experimental. Suramin had the benefit of being a 100-year old drug that could be tested in humans.
I want to emphasize that our research however was not about suramin. Suramin is just a tool that we have been using in our research to find an underlying cause for autism. It would obviously be wonderful if also it turns out to be a safe and effective useful drug for treating autism, but our work is really about examining the role of the Cell Danger Response (CDR) in autism and other conditions. Our work suggest that the CDR is at the heart of autism as well as other chronic conditions and may explain why these conditions have been rising over the past 30 years.
So what is the CDR?
The CDR is a natural and universal cellular response to any injury or stress. Its purpose is to help protect the cell and to jump-start the healing process. Our work suggests that sometimes the CDR gets "stuck" and block healing. This prevents completion of the natural healing cycle and can permanently alter the way the cell responds to the world. Like a wound that doesn’t heal, when this happens, cells behave as if they are still injured or in eminent danger, even though the original cause of the injury or threat has passed. You can think of this as a kind of cellular PTSD. If this happens during early child development, we believe it causes autism and many other chronic childhood disorders. When it happens later in life, a persistent CDR can lead to many other disorders. Other disorders we are studying that we also believe are related to the CDR are chronic fatigue syndrome (CFS), Gulf War Illness, and certain autoimmune disorders.
So what triggers the CDR in the first place?
Anything that injures or stresses the cell will activate the CDR. As you might expect, there are degrees of CDR severity that determine the intensity of the response. In its mildest form, physical exercise produces a transient activation of the CDR that “reminds” our bodies how to heal and improves our functional capacity by reinforcing natural connections between the brain, the gut, autonomic, the immune, musculoskeletal, pulmonary, and cardiovascular systems. Even learning at school produces a mild “stress” that results in cellular adaptations in the brain that build new synapses and trim others that help a child develop. A viral infection like a cold also activates the CDR. In the vast majority of cases, our bodies handle colds, cuts, or even a broken leg in a natural cycle that starts with the activation of the CDR, proceeds through several steps of healing, then turns off the CDR, returning us to health—often primed to be better able to handle the same or similar stresses in the future. Unusual chemicals in our food chain, water, and air can that have been accumulating in the past 30 years also activate the CDR. Even certain gene mutations increase the risk of a persistent CDR as the cell adapts to the mutation. One way to summarize the CDR in autism is that turning on the CDR is not the problem. It is the inability to turn the CDR off once it has served its purpose—to regulate it in a healthy way that is the problem.
What are the implications of this work?
There are quite a few implications of this work. The first and probably most important implication is that it suggests that some of the symptoms of autism are caused by a treatable metabolic syndrome. This represents a paradigm shift from how the medical community has traditionally viewed it.
Most people believe autism is a heterogeneous disorder, i.e., it's many different things, are you saying autism is actually just one thing?
When people talk about each child with autism as being unique, they are talking about symptoms that are not used for actual diagnosis of ASD. For example, some children with ASD have seizures, some have asthma, some have GI problems, some have failure to thrive, and some have problems with self-injurious behavior. These are important parts of their disease, but they are not core features of autism. The core symptoms are abnormalities in social communication, social interaction, repetitive or restricted behaviors, and/or sensory issues. These symptoms are used to diagnose 100% of children with ASD. We hypothesized that these core features that are present in 100% of children with ASD were caused by a common cellular response to environmental and genetic risk. So, on the one hand each child is unique. On the other hand, each child has the same core symptoms that allow doctors to diagnose autism spectrum disorder. We believe the CDR and abnormalities in purinergic signaling create a metabolic syndrome that is the root cause of ASD, no matter what the particular set of genes or environmental triggers a child has.
So do you believe autism is treatable or reversible?
I don’t like the term “reversible” because it implies a reversal of the arrow of time, which is not really what I mean. Effective treatments for autism must also include natural approaches for acquiring learning and development. We think of development in children with ASD as being blocked by an invisible plate glass window that diverts the child from one trajectory or path of development, and forces another. Suramin works by removing negative signals that block or slow natural child development. It is more like removing the brakes than pressing the accelerator. Accelerated catch-up development occurs when the brakes are removed because the child is ready to develop, but was otherwise blocked by their illness. This reminds me of giving a child who has an inborn error of metabolism, diseases I used to treat before focusing more on research, a vitamin or nutrient that they can’t make—the child begins to blossom. In some ways, it is like seeing a time-lapse video where the child makes progress in weeks that took months or years before.
We heard from parents that during the time the children were on suramin, their benefit from all their usual therapies and enrichment programs increased dramatically. Once suramin removed the roadblocks to development, the benefit from speech therapy, occupational therapy, ABA, and even from playing games with other children during recess at school skyrocketed. Suramin was synergistic with their other therapies.
Why was your study so small?
This work is new and this type of clinical trial is expensive. While we would have liked to do a larger study, we did not have enough funding. Fortunately, the goals of establishing basic safety, tolerability, and activity of suramin in autism were accomplished with just 10 subjects and the results look like they could be a game-changer. The results were so encouraging that they have caused me to rethink all that I was taught about autism in medical school.
What did this study cost, how did you fund it?
The trial cost $1.2 million over two years. This might sound like large number, but is relatively inexpensive for a trial as complex as this one was. We were able to keep the expenses low because more than 30 of the professionals who worked on the trial either volunteered their time or worked at a greatly reduced rate.
Still, I was only able to raise $700k so we were $500k short but we did the study anyway and had to go into debt to complete it. Funding came from a handful of non-profits [including N of One: Autism Research Foundation] and very dedicated parents and families that believed in our work. Unfortunately none of the usual major funding agencies supported our research. As a result of going into debt to fund the study, I've had to dramatically shrink my lab and slow our research progress greatly. We are currently working at only about 20% of our capacity if we actually had adequate funding.
Doesn't the university or med school pay for research?
Unfortunately not. What most people do not know is that while universities serve a wonderful role in both education and research, they for the most part do not directly support academic research. That's done through grants that researchers must apply for from the government, foundations, non-profits, and individuals.
What are the next steps in this research?
The next steps are to do additional, larger trials to see if these promising results continue to hold up and to collect all the data the FDA will need to decide about the approval of suramin for autism. These trials are very expensive, about $1 to $2 million per study at single sites. And multicenter studies will be needed, with commensurate increases in cost. We have plans to several more trials but the bottleneck is funding.
Even if suramin does not prove out as the best antipurinergic drug for autism, our studies blaze the trail for the development of new antipurinergic drugs that might be even better. Before our work, no one knew that purinergic signaling abnormalities were a part of autism. Now we do, and new drugs can be developed rationally and systematically.
If people want to help support this research, what can they do?
Work to get the next clinical trial done will either require a significant about-face from one of the major autism funders like NIH, or grass roots support from families and foundations, and other approaches to raise the needed funding. If people are interested in helping they can visit our website at www.naviauxlab.ucsd.edu for information about helping to support these studies.
What about teens and adults with ASD who don’t want to be treated but rather want to be accepted and appreciated for their unique talents, abilities, and differences?
ASD is a label we use to talk about a group of children and adults with a recognizable pattern of neurodevelopmental differences. In the extreme, some non-verbal children with ASD will grow up to be non-verbal adults who cannot speak for themselves and may not ever be able to care for their own daily needs or hold down jobs. In the other extreme, the special gifts of some children with ASD will lead them to become activists as teens and adults whose voice is highly sought out by local and national agencies to express the needs of others and to help guide progress. We had a gifted teen with ASD as part of the team on the SAT1 study. He is a graphic artist and helped us to design the storyboards that allowed each parent and their child to visually review and prepare for each step of the study with special attention to sensory issues that were important for children with ASD.
I have no desire to create new treatments for anyone who does not need or want treatment. I do not want to eliminate any symptoms or special gifts that someone wants to keep. The right to self-determination and the right to healthcare choice are fundamental freedoms. However, unless research can continue, new treatments will not be discovered, and the complementary freedom to choose a treatment when it is desired will be lost. We can respect both rights; the right to choose no treatment for some, and the right to choose new treatments for others. Both are possible, and both must be actively chosen to protect freedoms for all.
There is another point that needs to be made. In 2017, after over 70 years of trying, there are no effective pharmacologic treatments for the core symptoms of autism because a unifying theory for the cause of autism does not exist. People’s experience with ASD treatments to date have taught them that the treatment is often worse than the disorder. None of the treatments currently available actually get at the root problem in autism. If the root problem is ultimately proven to be the CDR and abnormalities in purinergic signaling, then the core symptoms like social fear, anxiety, and difficulties with verbal communication might be improved without suppressing the gifts that make children and adults with ASD exceptional. This new generation of treatments has a chance to precisely target the symptoms that hold people back with ASD, while not touching the gifts that allow them to excel.
Any Additional Thoughts?
Autism often affects children who have shown early gifts, and might otherwise grow up to become some of the best and brightest of their generation. Even if this is only true for a fraction of children, it means that some children now living with disabling forms of ASD, whose parents fear they might never be able to live independently, could have a chance for independence and live happy, self-reliant lives. And because many children with ASD are locked in by their symptoms, these children, once freed from their most disabling symptoms, might be just the ones the world needs to solve the greatest problems facing our planet in the next century.
I believe that autism is the key to understanding a large number of chronic, complex diseases that have no single genetic cause. Modern medicine is good at treating things that can kill you fast. But modern medicine is bad at treating things that kill us slowly, or change lives for years or a lifetime. I believe the reason for this is that the rules of acute care medicine rely on the body’s natural healing pathways to remain intact. This requirement does not hold for chronic disease. In chronic disease, the normal healing cycle is blocked, so full recovery, when treated with current medicines, almost never happens.
Autism has taught me that if the cell danger response (CDR) remains on, then healing, or the return to normal child development, is blocked. If we unblock healing by turning down the CDR, then dramatic improvements can occur. I believe autism is the key to understanding over half of all chronic disease, in children and adults alike. If I am right, then this work will open not just a new chapter, but a new book of medicine that uses a molecular and metabolic understanding of healing and regeneration to prescribe completely new treatments that can improve or eliminate some diseases in months that today we can only treat with modest effect for a lifetime.”
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The views and opinions in these interviews are not necessarily those of N of One: Autism Research Foundation and should not be construed as medical advice or recommendations. Be aware that reatments that may help one child may have adverse effects in another. Before beginning any type of treatment regimen, natural or conventional, it is advisable to seek the advice of a licensed healthcare professional.