Low dose suramin and autism: a small RCT with potentially big results

'Low dose' has been a feature of my autism research reading this week; first starting with the results from Dan Quintana and colleagues [1] talking about some important effects following intranasal delivery of low dose oxytocin and then moving on to the primary reason for this entry with results from Robert Naviaux and colleagues [2] (open-access) continuing a research theme looking at suramin and autism (see here for some background).

For those interested in the oxytocin-autism research base, I can recommend following Dr Quintana on Twitter (find him here).

In relation to the Naviaux findings  - the "Suramin Autism Treatment-1 (SAT-1) trial" - well, they are open-access but I want to provide some overview and then a little bit of discussion. I might add that this research team are making research waves in several areas of medical science as per their research foray into chronic fatigue syndrome (CFS) recently (see here). Such 'metabolomic' research is pertinent to their autism research too.

This time around as on previous research occasions, the focus was on suramin - the "century-old sleeping sickness drug" - and, as far as I can see, the first time said drug has been tested experimentally with children diagnosed with an autism spectrum disorder (ASD). The accompanying ClinicalTrials.gov trial entry is here.

As per the title to this blog entry, this was a small trial including only 10 participants, all male, aged between 5-14 years old. This was a randomised-controlled trial (RCT) with a placebo element to it too, so half of the participants got suramin - "a single, intravenous infusion of suramin (20 mg/kg)" - and half got saline as a control. Alongside looking at behaviour and functioning, researchers also took blood and urine samples "for safety and toxicity monitoring at 5 times throughout the study." This was accompanied by quite a bit of effort to look at the possibility of adverse events related to suramin or placebo administration.

Results: "A single intravenous dose 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. None of these improvements occurred in the five children who received placebo." The authors also do the right thing by stating: "The generalizability of these findings is unknown." I'm particularly impressed that the ATEC gets a showing given the rise and rise of this autism research tool (see here) in various placebo-controlled contexts (see here).

In relation to the safety aspect to suramin, well, it seemed to do alright. We are told that: "Extensive monitoring revealed no serious toxicities" so one can assume that the 'first, do no harm' tenet was upheld in this trial. But there was one important side-effect noted: "Five children who received suramin developed a self-limited, evanescent, asymptomatic, fine macular, patchy, morbilliform rash over 1–20% of their body." The rash was short-lived and did not require specific attention/intervention but it's worthwhile noting it especially when nothing similar was reported in the placebo group.

Going back to the mention of this research group delving into CFS with metabolomics in mind, so similar results are reported on the basis of examination of plasma samples from participants. Various biological pathways seemed to be affected by the infusion of suramin, not least "the importance of the cell danger response (CDR) [3]... and purinergic signaling." Interestingly, authors also noted effects in relation to "1-carbon, folate, methionine, and cysteine metabolism" too, potentially linked to other findings independently reported in relation to autism (see here for example).

Reiterating again that this was a small study (albeit using the gold-standard in scientific methodologies) these results are rather interesting and potentially quite important. They most definitely point to the requirement for further large-scale studies to look at any effects in a larger participant group and to 'zoom in' on potential best-responders to this type of intervention. I end with an important conclusion from the authors who again, have not over-stated their findings:

"Suramin is not approved for the treatment of autism. Like many intravenous drugs, when administered improperly by untrained personnel, at the wrong dose and schedule, without careful measurement of drug levels and monitoring for toxicity, suramin can cause harm. Careful clinical trials will be needed over several years at several sites to learn how to use low-dose suramin safely in autism, and to identify drug–drug interactions and rare side effects that cannot currently be predicted. We strongly caution against the unauthorized use of suramin."

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[1] Quintana DS. et al. Dose-dependent social-cognitive effects of intranasal oxytocin delivered with novel Breath Powered device in adults with autism spectrum disorder: a randomized placebo-controlled double-blind crossover trial. Transl Psychiatry. 2017 May 23;7(5):e1136.

[2] Naviaux RK. et al. Low-dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial. Annals of Clinical & Translational Neurology. 2017. 26 May.

[3] Naviaux RK. Metabolic features of the cell danger response. Mitochondrion. 2014; 16: 7-17.

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Naviaux, R., Curtis, B., Li, K., Naviaux, J., Bright, A., Reiner, G., Westerfield, M., Goh, S., Alaynick, W., Wang, L., Capparelli, E., Adams, C., Sun, J., Jain, S., He, F., Arellano, D., Mash, L., Chukoskie, L., Lincoln, A., & Townsend, J. (2017). Low-dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial Annals of Clinical and Translational Neurology DOI: 10.1002/acn3.424

More suramin and autism [mouse] findings

The headline: 'Century-old drug reverses signs of autism in mice' brought the paper by Jane Naviaux and colleagues [1] (open-access) to my attention and some slightly familiar work (see here) on the use of suramin in a mouse model of autism, or rather a mouse model of maternal immune activation. Indeed, I seem to remember that the previous study by this group [2] courted similar publicity, with some familiar headlines...

Not lecturing... @ Wikipedia 

The latest offering from Naviaux et al is not so dissimilar from their previous work on that mouse model of autism, this time testing "the hypothesis that the behavioral manifestations of the MIA [maternal immune activation] model are a consequence of pathological persistence of the evolutionarily conserved CDR [cell danger response]... and that the CDR is maintained by dysregulated purine metabolism and secondary abnormalities in purinergic signaling". The press release about the study can be viewed here.

What this all translates into is that a state of immune arousal above and beyond what would be typically expected during pregnancy is somehow impacting on offspring development pertinent to an elevated risk of conditions like autism or schizophrenia. There is quite a bit of literature on this topic from the autism perspective (see here) and based on animal models other than just rodents (see here). The cell danger response (CDR) described by Naviaux (Robert that is) [3] represents "the evolutionarily conserved metabolic response that protects cells and hosts from harm". Indeed that last reference [3] contains just about every biological link known to autism science at the current time... including mitochondria. The idea is that triggering immune activation activates "a conserved cellular response to stress" called the CDR and the proposed master regulator of the CDR is purinergic signalling [4] - "purine nucleotides and nucleosides as extracellular messengers". ATP (adenosine triphosphate) as well as being quite an important molecular fuel source, is suggested to be one of the nucleotides which "can bind to cell surface receptors and act as signaling molecules and neuromodulators that are important in inflammation.. neurotransmission.. and many other biological processes".

A few basic points about the Naviaux study:

• Mice were the lucky volunteers for this study, and again the 'good breeder' that is the C57BL/6J variety. As per their previous trial, pregnant female mice were given something to artificially stimulate their immune system and "initiate the MIA model" or a saline control and then their offspring were the study focus.
• Suramin or saline (as a control) was then administered to 6-month old offspring mice and thereafter "behaviors were evaluated". Suramin levels were also examined, as were a broad range of metabolites as part of some metabolomic analysis based on the use of triple quad mass spectrometry.
• Results: "MIA animals showed social deficits from an early age". Nothing too novel there bearing in mind previous observations in this area of research. But... "Single-dose APT [antipurinergic therapy] with suramin completely reversed the social abnormalities in 6.5-month-old adults". Social behaviour by the way, was quantified as "time spent interacting with a novel ("stranger") mouse".
• The benefit of suramin also lasted for quite a while: "a small residual benefit to social behavior was still detectable" even after 5 weeks following the intervention. There is some discussion by the authors about this effect; noted to be potentially "due to the development of metabolic memory and/or somatic epigenetic DNA changes that lasted longer than the physical presence of the drug".
• Then the biochemistry. Suramin seemed to by-pass that very important gateway, the blood-brain barrier (BBB) and end up in the brainstem following some analysis of sacrificed offspring mice: "consistent with the notion that nuclei in brainstem, or their projection targets in distant sites of the brain, may mediate the dramatic behavioral effects of acute and chronic APT in this model".
• And more: "Comprehensive metabolomic analysis revealed disturbances in several other metabolic pathways relevant to children with ASDs. These included disturbances in microbiome, phospholipid, cholesterol/sterol, sphingolipid, glycolytic and bile salt metabolism". This bearing in mind that only "male animals that had been behaviorally evaluated were tested". Purine metabolism and the gut microbiome seemed to be quite important to the author's results. At this point I'll refer you back to the work by Elaine Hsiao and colleagues... 
• Moreover: "The top, non-microbiome-associated metabolite was quinolinic acid... which was decreased in the MIA model". Quinolinic acid implies the involvement of one of those aromatic amino acids, tryptophan, which is an autism research favourite [5]. More than that is the literature on the intersecting kynurenine pathway and how that might relate to a condition like schizophrenia (see here).
• The authors caution that their results are (a) mouse based and (b) "suramin is a poor drug choice for chronic use because of potentially toxic side effects that can occur with prolonged treatment". That being said, they do suggest that "new drugs might be given only once, or intermittently, during sensitive windows to unblock metabolism, restore more normal neural network function, improve resilience and plasticity, and permit improved development in response to behavioral and interdisciplinary therapies, and to natural play". Just in case you'd like an alternative reading of this study, have a look at this write-up too.

I do apologise for all the quotes taken from the Naviaux paper and used in this post, but when the authors say it better than I could, why would I try and complicate things any further? Indeed, the more I read the paper by Naviaux and colleagues, the more I see what a potential gem it actually is. I say this based on the pretty comprehensive way that the authors went about looking at the MIA model and the effect of their intervention, crossing behavioural (mouse behavioural) and biochemical fields. Mention of the words 'microbiome' and 'metabolome' are also guaranteed to perk my interest. All that enthusiasm is however tempered dependent on the work being replicated and not just in a mouse model either.

A few closing comments are all that are required. Looking at the list of biochemical pathways altered in the MIA model of autism (see Table 1 here) we see lots of familiar names too numerous to mention. Outside of looking at the effect of suramin on these pathways, I'm minded to suggest that other interventions might also benefit from some similar inspection of their effects on said pathways. Even as one commentator has already noted: "[The findings] are valuable, but the main problem is that they rely on a model of immune infection, not a genuine model of autism... They should have tested one of the classical models of autism... meaning genetic models of autism — to see whether suramin indeed corrects autistic behaviors".

I've also not really gone into the detail when it comes to the cell danger response (CDR) in this post because it is a complicated area and seems to tie into various issues which are slightly beyond my level of expertise. I would like to bring in the letter by Theoharides [6] at this point however, and his discussion linking "extracellular mitochondrial material" to mast cell activation (see here) on the back of the previous study by this authorship group, as another area crying out for further investigation.

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[1] Naviaux JC. et al. Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy. Translational Psychiatry. 2014; 4: e400; doi:10.1038/tp.2014.33

[2] Naviaux RK. et al. Antipurinergic therapy corrects the autism-like features in the poly(IC) mouse model. PLoS One. 2013;8(3):e57380.

[3] Naviaux RK. Metabolic features of the cell danger response. Mitochondrion. 2014 May;16:7-17.

[4] Burnstock G. Pathophysiology and therapeutic potential of purinergic signaling. Pharmacol Rev. 2006 Mar;58(1):58-86.

[5] Boccuto L. et al. Decreased tryptophan metabolism in patients with autism spectrum disorders. Mol Autism. 2013 Jun 3;4(1):16.

[6] Theoharides TC. Extracellular Mitochondrial ATP, Suramin, and Autism? Clinical Therapeutics. 2013; 35: 1454-1456.

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Naviaux JC, Schuchbauer MA, Li K, Wang L, Risbrough VB, Powell SB, & Naviaux RK (2014). Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy. Translational psychiatry, 4 PMID: 24937094