The Significance of Reversing Autism-Like Features in Two Distinct Mouse Models With a Single Drug, Suramin
Finding suggests that a reversible metabolic syndrome
may be at core of autism -- challenging current view
Update May 2017: Trial Complete. Results Published
Update July 2015: Human Trials Are Now Underway
January 15th, 2015
A review and commentary on: “Antipurinergic therapy corrects the autism-like features of the
Fragile X (Fmr1 knockout) mouse model”
by John Rodakis, Founder N of One: Autism Research Foundation
It’s possible that the world of autism is different today. It’s also possible that the potential significance of the most recent research paper from the eminent autism researcher Robert Naviaux, MD Ph.D from UCSD School of Medicine could get lost in the technical details. While his findings could turn out to be another interesting, but insignificant blip on the tortuous road of autism research; It is also possible that Dr. Naviaux may have just changed everything about autism research and that we need to pay close attention to what happens next.
In March of 2013 Dr. Robert Naviaux, who is a professor of genetics and Co-Director of the Mitochondrial and Metabolic Disease Center at the University of California, San Diego School of Medicine, published a paper that fascinated many autism researchers around the world.
He found that a 100 year old drug called suramin, most commonly used to treat African sleeping sickness, reversed virtually all of the autism-like symptoms of a well-studied autism mouse model called the MIA mouse. It was a stunning finding but raised many questions for researchers. Some researchers questioned whether it had direct applicability to autism in humans, especially given concerns about suramin's long term side-effect profile.
Dr. Naviaux, who has said suramin is not a good long term drug for autism, has been using suramin primarily as a research tool because of some of its unique properties (discussed below) and what he is finding may shed light on what is at the core of autism.
Today, Dr. Naviaux announced that this same drug, suramin, produced similar improvements in a completely different autism mouse model, one based on the genetic syndrome of Fragile X.
The difference between these two mouse models is significant. In the first case, the MIA mice develop autism-like symptoms because of what they are exposed to in utero; while in the Fragile X model, because of genetic changes in the mice's DNA. When one drug works on two completely different models of a disease, it suggests that it is working in a common way, on a common core pathway of the disease - which for years has been elusive in autism research. It also increases the likelihood that what he is doing in these mouse models may be directly applicable to humans, again with the caveat that long-term use of suramin in humans is not a good option..
The MIA mouse
MIA is an acronym for Maternal Immune Activation. The MIA mouse is a mouse model of autism that was developed by the recently-deceased, legendary neurobiologist Dr. Paul Patterson from Cal Tech. Dr. Patterson became interested in the finding that infection during pregnancy increased the risk of neuro-developmental disorders like autism in children. He followed this clue to see if he could replicate the effect in animals and in 2007 published the first of many papers that showed that by “tricking” a pregnant mouse’s body into thinking that it was being infected, the male offspring of that mouse would exhibit many of the same behavioral, biochemical, and gene expression abnormalities that were seen in autism. The "trick" involved using an infectious mimic of either a virus (using PolyIC - which is double-stranded RNA that does not code for anything) or a bacteria (using LPS - a piece of the external coat of a bacterium). Dr. Naviaux used PolyIC, but other have used LPS.
Over the years, other researchers, including Dr. Naviaux, further investigated these mice and continued to document autism-like features [see Figure "Making "autistic" mice].
The biological basis of how all of these autism-like abnormalities occur (and why they favored the male mice) is to this day unknown. Some believe that autism-like features are strictly a byproduct of the traditional immune system. We at N of One: Autism Research Foundation believe that in addition to immune system changes, early alterations to the gut microbiome are at play. However one thing is generally agreed upon, the changes are not being caused by genetics. The mice were all genetically identical to both each other and their controls; hence there could be no primary genetic cause of the mice’s autism-like features.
Suramin and Young MIA Mice (2013)
In 2013 Robert Naviaux published a paper with the rather wonky sounding title: Antipurinergic Therapy Corrects the Autism-Like Features in the Poly(IC) Mouse Model which documented experiments in which he gave suramin to young MIA mice. One of the most intriguing aspects of the paper is that the suramin almost completely reversed virtually all of the autism-like abnormalities observed. A question for most in the field was: “Why Suramin?” What did Dr. Naviaux think was going on that led him to try a 100 y.o. drug primarily known for its anti-parasitic properties?
Normally, pharmaceutical companies screen thousands of potential compounds against a disease model to identify promising candidates. It’s a shotgun type of approach and something that biotech and pharmaceutical companies do well. The decision to try suramin however was not the result of such an effort. It was more of a “snipershot.”
Dr. Naviaux had a novel theory as to what may be behind both autism and the mice’s abnormalities that led him to try suramin. Dr. Naviaux’s theory was that individual cells in the body had a means of sensing danger or threats for example from an invading virus or bacteria (think the government's terror threat level) and that when danger was sensed, the cell would shift into an altered state (red alert!) that promoted its defense and survival. His term for this defensive state, which other researchers have also studied, is the Cell Danger Response (CDR). Dr. Naviaux proposed that in certain cases, when invoked early in development, the CDR could get stuck or remain chronically activated leading to abnormal development. An analogy might be to think of a country permanently on a war-time footing: It might get really good at making bombs and defending itself, but other more normal peacetime activities, e.g., maintaining road, libraries, etc, might suffer.
Dr. Naviaux also believes that tiny sub-components of the cell called mitochondria - which we learned in high school biology are the “powerhouses” of cell - were the prime regulators of this CDR (think of the Department of Defense or the Pentagon). He also believed that one of the primary danger sensing mechanisms of the cell is to sample and measure (taste, if you will) the amount of purines, like ATP (which we also learned from high school biology is the primary energy carrier in the body) outside of the cell. The taste buds in this system are receptors (or detectors, if you like) mounted to the outside of the cell called P2Y receptors. More purines outside the cell = more danger = more CDR.
While it sounds complex, there is some intuitive logic to the theory: Purines are important to cells (energy transfer, building DNA, etc) all things being equal, they’d like to keep them inside. If there are a lot of purines floating around outside the cell, it may mean that nearby cells are getting destroyed.
Dr. Naviaux reasoned that if you could turn this threat detector off (or at least keep it busy doing something else by finding something else that would also bind to it instead of the purines) the CDR might also turn off. This is a common approach in pharmaceutical development, it’s called competitive inhibition and is the basis for many of today’s most effective drugs. Suramin is a drug that is approved for use in humans, albeit with dangerous long-term side-effects. It is also known bind to these receptors and so Dr. Naviaux tried it in the mice to test his theory.
The MIA mice were given suramin once a week for 10 weeks and compared to controls. While receiving suramin, all of the observed and measured behavioral abnormalities normalized. The blood biochemistry abnormalities commonly seen in both MIA mice and many ASD patients also normalized. However, the abnormalities returned following removal of the suramin.
After the 10 week administration, the animals brain structure was compared to controls. Remarkably, the mice given suramin had begun to regrow a type of brain cell, called purkinje cells, which MIA mice and ASD children are known to be deficient in. The message seemed clear, suramin was working at a deep, fundamental biological level when and while given at an early age in MIA mice.
Suramin and Adult mice (2014)
In June 2014 Dr. Naviaux et al published a second paper on suramin and the MIA mouse: “Reversal of autism-like behaviors and metabolism in adult mice with single dose antipurinergic therapy ”. This time he was asking a different question: Would suramin also produce benefits in older mice and if so, how long would they last?
He gave a just a single dose of suramin to 6 month old mice, which are considered equivalent to 30 y.o. in humans. These mice achieved many of the same improvements as the young mice in the previous experiment, though not the complete reversal seen in the young mice experiments. [see table below: Summary of Mouse Observations from Naviaux Experiments]. The suramin reversed the behavioral abnormalities rapidly. The improvements lasted for about 6 weeks after the single dose.
This is significant because the commonly held view is that autism is a neurodevelopmental disorder whose abnormalities are primarily a function of brain development and are largely set by adulthood. The fact the improvements were rapid and in adults challenges the conventional view that autism's abnormal behaviors are a function of abnormal brain wiring and largely irreversible beyond a certain early age. A potentially hopeful finding for those with severe ASD in adulthood.
Fragile X is not autism and autism is not fragile X. Fragile X is a genetic condition that can be diagnosed via genetic testing from a blood draw. Autism is a diagnosis based on behavioral symptoms for which there is no blood test. Someone with fragile X can, and often will, be diagnosed with autism (CDC Parent survey estimates 46% for boys; 16% for Girls). Someone with autism will be found to have fragile X syndrome <5% of the time. Despite these important differences, there does seem to be substantial overlap in symptoms and behaviors and the two are often investigated together.
Fragile X occurs when there is a mutation in the FMRP1 (fragile X mental retardation) gene. The mutation is usually because of a series of repeated DNA letters that interferes with proper gene expression. Researchers discovered that they could create a mouse model for fragile X by disabling or "knocking out" the FMRP1 gene in a mouse. The mice exhibit many of the same autism-like characteristics (including biochemistry) as the MIA mice.
In his most recent paper, Dr. Naviaux gave the fragile X knockout mice suramin and recorded the changes in their behavior and blood chemistry. Like the MIA mice, the fragile X mice that received suramin also saw improvements in behavior and biochemistry that continued while the suramin was being giving and continued for a period of time after the suramin was discontinued (see table).
As described above, the MIA mouse is considered to be an environmental model of autism, that is, there is nothing special about the MIA mice prior to their in-utero exposure of the infectious mimic. They are that way because of what happened to them. The fragile X mouse is considered to be a genetic model of autism, that is the mice were pre-determined to have fragile X and can never be cured of that underlying mutation. Suramin seems to improve abnormalities seen on both models which suggests it is working at a very deep, fundamental level - perhaps at the very core of what manifests itself as autism. This may be the so called "final common pathway" of autism that has been theorized to exist.
Why is this significant?
It is significant because Dr. Naviaux's view differs rather meaningfully from the conventional view of autism which holds that autism is primarily a neuro-developmental disorder that arises from genetic alterations that are largely irreversible. Dr. Naviaux instead believes that what is "going wrong" in both mouse models is a metabolic syndrome that he calls the cell danger response that gets chronically activated. Dr. Naviaux believes further believes that this cell-driven cascade or syndrome is behind human autism and can be triggered any number of ways including, perhaps, even by certain types of DNA damage or abnormalities such as those seen in the fragile X model. This "moves the culprit" from FMRP gene per se and to the cell danger response thus providing a downstream target or unifying mechanism for autism research.
The implications of this idea are staggering because much of the autism biomedical research in the US is focused on trying to identify specific gene mutations that may be associated with autism and then painstakingly studying the products of those suspect genes to see how they may lead to autism. However, to date, this research has not revealed any mutations that account for more than few percent of cases of autism and for those genes that have been implicated, a unifying mechanism by which they might lead to autism has been elusive. Is it possible that some of those mutations that have been observed could be involved in proper functioning of the cell danger response?
Dr. Naviaux's findings: i) potentially move the focus of such research from the DNA to the cell's metabolism, ii) provides researchers a new, rich set of targets for study and iii) provides hope for improvements for parents and patients despite an underlying genetic condition. Is Dr. Naviaux right? Time will tell, but given his track record, I think we should start paying very close attention to what he does next.
The way forward
Is the world of autism research really different today? Perhaps, but so far, this is only mouse model work, and mice are not humans. The real test will come later in 2015 when suramin is scheduled to be tested in humans with ASD. The first trial will be a small trial and subjects will only receive a single dose of suramin to minimize the potential for side-effects. Even if this trial is successful, if the mice are any indication, it will only have a temporary benefit. Researchers would then need to investigate if suramin can be given safely in this population or if other compounds that work similarly to suramin can be developed. While there are no guarantees, it would be a promising research avenue and perhaps mark a much-needed breakthrough for autism.
N of One: Autism Research Foundation is a non-profit sponsor of promising emerging medical autism research including research into the Cell Danger Response. N of One has additional studies planned with Dr. Naviaux. Individuals and entities interested in sponsoring this research should contact N of One: Autism Research Foundation or can donate directly from this site.
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Dr. Naviaux's Original Paper can be found here