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.