Headline fail: "Autism traits could be 'edited' out genetic trial suggests"

The Telegraph June 25 2018

"Autism traits could be 'edited' out genetic trial suggests" was one of the headlines that accompanied the publication of the findings by Bumwhee Lee and colleagues [1].

The Lee article details some interesting science following the use of something called CRISPR-Cas9 gene editing (see here) or more precisely the use of a new-ish development to this technique - "CRISPR–Gold, a nonviral delivery vehicle for the CRISPR–Cas9 ribonucleoprotein." CRISPR is one of the hottest things in science at the moment, as the words 'find, cut and paste' move to a genetic level (see here) and promises so much. In the Lee study, the target was the metabotropic glutamate receptor 5 (mGluR5) gene as a move to "efficiently reduce local mGluR5 levels in the striatum."

Oh, did I also mention that this research was done using mice? Indeed, this was a study of mice engineered to display some of the molecular and behavioural characteristics of a condition called Fragile X syndrome (FXS). As such, authors reported that the use of CRISPR-Gold injections into the striatum of said FXS mice correlated with a reduction in certain behaviours such as obsessive digging and leaping into the air. The authors opine that such behaviours 'overlap' with those noted in autism (FXS has a 'connection' to autism) and voilà, a link to autism is made.

Aside from that brief overview of the findings from Lee et al just mentioned, I'm not going to go too much into the nitty-gritty of the actual results. A cobbler should stick to his last and all that, and others have done a far better job than I ever could in discussing the science (see here). I do however want to make a case that the 'autism traits could be edited out' headline represents a fail when covering the Lee findings.

I say 'headline fail' in the title of this post because well, it is. Not only does it assume that obsessive digging and sporadic leaping into the air made by mice are singularly autistic traits, it takes a few sentences before the word 'mice' is even mentioned in the coverage. I've talked before about the caution(s) needed when translating animal findings to real people (see here) and how autism in particular, seems to be a label ripe for mass sweeping generalisations from 'autistic animals' to autistic people. I'm not saying that some of the features of autism are uniquely human (see here) but rather that is it premature to even imply that the traits of autism can be 'edited out' on the basis of a single mouse or other animal genetic study.

I've already mentioned about a 'connection' between FXS and autism but it is perhaps also important to realise that there seem to be many routes that bring someone to a diagnosis of autism. FXS is one condition that manifests autistic traits but it is not the only one and certainly science does not yet know everything there is to know about the genetics of autism and FXS. And just before anyone starts talking about autism being universally 'in-born' and 'genetic' as it is [assumed] in FXS, well, the peer-reviewed research evidence might just disagree with you (see here for one example)...

Finally there's another aspect to this work that requires sensitive media handling: the ethics of 'editing out' autistic traits. I know this is a 'hot potato' area, as an increasingly vocal - certainly on social media - group of people on the autism spectrum talk about their strengths as well as their disabilities. Much of this discussion is framed around the notion that autism is not something separate from who they are but rather a fundamental part of who they are. If one takes this viewpoint, it is logical to assume that 'editing out' autistic traits might mean something rather ominous to some people...

The point I'm trying to get across is that the Lee paper is seemingly good science. It faithfully reported the results of an exciting new technology that holds promise for many different labels, conditions and diseases (see here). The issue however, is that the reporting of such research needs to be accurate and responsible. Headlines in particular, need to mention the word 'mouse' if it was a mouse study. They need to avoid sweeping generalisations that infer that digging and leaping behaviour in animals are generalisable as autistic traits (certainly the latest ICD-11 schedule says nothing about such behaviours), and they need to be sensitive to the fact that 'editing out' may very well provoke significant anxiety among some people on the autism spectrum. All for the sake of an attention-grabbing headline...

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[1] Lee B. et al. Nanoparticle delivery of CRISPR into the brain rescues a mouse model of fragile X syndrome from exaggerated repetitive behaviours. Nature Biomedical Engineering. 2018. June 25.

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Autism manifests across a range of genetic and metabolic syndromes

"Autism spectrum disorder (ASD) phenomenology is reported to be more common in individuals with some genetic syndromes than in the general population."

That was the starting point for the systematic review and meta-analysis published by Caroline Richards and colleagues [1] who set about 'synthesising' the various peer-reviewed data "to provide accurate estimates about ASD phenomenology in genetic and metabolic syndromes." A scan of the cumulative literature in this area ("168 papers reporting the prevalence of ASD phenomenology") revealed that autism presentation is indeed a feature of quite a few conditions compared with "the general population taking the current estimate of one in 68 people."

To those with an eye on the autism research scene the list of conditions where autism manifests is not likely to be a surprise. Rett syndrome represented one of the conditions where relative risk and odds ratio "compared to the general population" was highest. Tuberous sclerosis (TS) is also mentioned as is neurofibromatosis type 1 (NF1). I was however a little surprised that Fragile X syndrome was a little further down the frequency line than it was - "male individuals only 30%; mixed sex 22%" - given the quite classical association that I remember being discussed with autism. Down syndrome is also mentioned and perhaps reflects an increasing interest in autism being comorbid that has graced this blog previously (see here) as has the growing connection with Del22 (see here).

The authors conclude by calling for more research "including how ASD in genetic and metabolic syndromes differs from idiopathic autism [autism spontaneously arising with unknown aetiology] and what that can tell us about the mechanisms underlying ASD." This is a discussion also included in a recent paper by Sacrey and colleagues [2]. I would agree with those sentiments within the context of the Richards paper providing more evidence for the plurality of autism - the autisms (see here). I might add that if one extends the findings to autism comorbid to metabolic disorders (as in conditions such as the various inborn errors of metabolism) (see here), further details may indeed be revealing about just how many types of autism there may be, and where desired, what intervention options may present (see here).

Music: The Lumineers - Ho Hey.

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[1] Richards C. et al. Prevalence of autism spectrum disorder phenomenology in genetic disorders: a systematic review and meta-analysis. Lancet Psychiatry. 2015. Sept 1.

[2] Sacrey LR. et al. Early Infant Development and Intervention for Autism Spectrum Disorder. J Child Neurol. 2015 Aug 31. pii: 0883073815601500.

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Caroline Richards, Christopher Jones, Laura Groves, Jo Moss, & Chris Oliver (2015). Prevalence of autism spectrum disorder phenomenology in genetic disorders: a systematic review and meta-analysis The Lancet Psychiatry

Suramin and the Fragile X (Fmr1 knockout) mouse model (and autism)

Fancy some weekend reading? Well, you could do a lot worse than having a gander through the paper by Jane Naviaux and colleagues [1] (open-access) discussing the results of a whole host of analyses following the use of the antipurinergic agent suramin on a mouse model of Fragile X syndrome.

Overprotective mother, forbidden road trip...

Regular readers might remember some previous discussions about suramin - a pharmaceutic designed to treat African sleeping sickness - and autism which have graced this blog (see here and see here). Following a series of studies which looked at the physiological and behavioural effects of suramin administration on a mouse model trying to recreate conditions of maternal immune activation (MIA (which itself has some autism research history), authors this time turned their attention to a mouse model of Fragile X syndrome, a condition which can in humans manifest with autistic traits (sometimes).

The Naviaux paper is a whopper in terms of data accumulated and results so I'm not going to even try and summarise the findings aside from quoting the authors that their: "results support the novel conclusion that antipurinergic therapy is operating by a mechanism that lies close to the root cause of the core behaviors and development in both the environmental MIA, and the genetic Fragile X models of ASD [autism spectrum disorder]. This mechanism appears to be traceable to mitochondria and regulated by purinergic signaling." Both mitochondrial and purinergic issues have featured in the autism research historical tapestry before (see here and see here respectively).

Just before anyone makes a run on suramin, I might however point out a few things: (a) the current and previous results are based on mouse studies and mice are mice not humans, and (b) suramin, whilst indicated for sleeping sickness, is not without the possibility of some pretty important side-effects (see here).

Still, this latest paper again potentially opens up a number of promising lines of inquiry in need of further investigation. And the added bonus is to see some more metabolomics included in their results!

To close: INXS and Mystify.

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[1] Naviaux JC. et al. Antipurinergic therapy corrects the autism-like features in the fragile X (Fmr1 knockout) mouse model. Molecular Autism 2015, 6:1

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Jane C Naviaux, Lin Wang, Kefeng Li, A Taylor Bright, William A Alaynick, Kenneth R Williams, Susan B Powell, & Robert K Naviaux (2015). Antipurinergic therapy corrects the autism-like features in the fragile X (Fmr1 knockout) mouse model Molecular Autism : 1186/2040-2392-6-1

Omega-3 fatty acids rescues Fragile X phenotypes in Fmr1-Ko mice

"These results demonstrate that n-3 PUFAs dietary supplementation, although not a panacea, has a considerable therapeutic value for FXS [Fragile X syndrome] and potentially for ASD [autism spectrum disorder], suggesting a major mediating role of neuroinflammatory mechanisms".

A view @ Wikipedia 

That was the conclusion reached by Susanna Pietropaolo and colleagues [1] who "evaluated the impact of n-3 PUFA dietary supplementation in a mouse model of fragile X syndrome (FXS), i.e., a major developmental disease and the most frequent monogenic cause of ASD". Looking at the Fmr1-KO mouse model of FXS, a mouse specifically bred to mimic the silencing of the FMR1 gene noted in FXS (see here) with onwards adverse effects for the production of FMRP, researchers looked at what happened when diets were "enriched or not with n-3 PUFAs from weaning until adulthood when they were tested for multiple FXS-like behaviors". The results seemed to indicate that "n-3 PUFA supplementation rescued most of the behavioral abnormalities displayed by Fmr1-KO mice, including alterations in emotionality, social interaction and non-spatial memory, although not their deficits in social recognition and spatial memory". Neuroinflammatory imbalances noted in the knock-out mice were also positively affected by omega-3 supplementation.

I don't need to remind you that the Pietropaolo study was a study of mice and one needs to be quite careful about extrapolating animal results when it comes to humans. That being said, given the quite extensive work that has been done on FXS and the detailing of it's molecular background, one might assume that the current results are treated with a little less scepticism than in relation to other more idiopathic 'types' of autism. Still, proper trials with people are indicated as per other research.

Omega-3 fatty acids have been discussed before on this blog with autism in mind (see here). The collected literature on their usefulness as supplements for autism is rather mixed at present [2] despite some emerging evidence on their involvement in various biological processes in cases of autism (see here). That being said, I'm not getting too down on omega-3 fatty acids in light of some associations being made with specific skills over and above any condition-specific relationship and some new light being shed on their use in other conditions [3]. I'm yet to find anything like an experimental trial of fatty acids in real people with FXS but did chance(!) upon the study by Lachance and colleagues [4] (open-access) talking about the use of fenretinide (N-(4-hydroxyphenyl) retinamide (4HPR)) in the test-tube and effects "associated with the normalization of arachidonic acid/docosahexaenoic acid ratio in macrophages". The effect talked about translates as a down-regulation in the "production of arachidonic acid (AA), a pro-inflammatory omega-6 polyunsaturated fatty acid, and to increase levels of omega-3 polyunsaturated docosahexaenoic acid (DHA), which has an anti-inflammatory effect". Mmm... possibly some new targets to replace quite a few disappointments when it comes to FXS therapeutics (see here).

Music to close. Fontella Bass and Rescue Me.

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[1] Pietropaolo S. et al. Dietary supplementation of omega-3 fatty acids rescues fragile X phenotypes in Fmr1-Ko mice. Psychoneuroendocrinology. 2014 Jul 9;49C:119-129.

[2] James S. et al. Omega-3 fatty acids supplementation for autism spectrum disorders (ASD). Cochrane Database Syst Rev. 2011 Nov 9;(11):CD007992.

[3] Hawkey E. & Nigg JT. Omega-3 fatty acid and ADHD: Blood level analysis and meta-analytic extension of supplementation trials. Clin Psychol Rev. 2014 Jun 2;34(6):496-505.

[4] Lachance C. et al. Fenretinide corrects the imbalance between omega-6 to omega-3 polyunsaturated fatty acids and inhibits macrophage inflammatory mediators via the ERK pathway. PLoS One. 2013 Sep 12;8(9):e74875.

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Pietropaolo S, Goubran MG, Joffre C, Aubert A, Lemaire-Mayo V, Crusio WE, & Layé S (2014). Dietary supplementation of omega-3 fatty acids rescues fragile X phenotypes in Fmr1-Ko mice. Psychoneuroendocrinology, 49C, 119-129 PMID: 25080404

All eyes on minocycline

Minocycline, the tetracycline antibiotic, is probably not something that most people would traditionally link with autism or conditions presenting with autism-like behaviours. Indeed, the suggestion that antibiotics or antimicrobials if you prefer, may be able to modify either the behaviour or linked biochemistry of the autism spectrum disorders (ASDs) or even influence the onset and expression of ASD is quite frankly a little bit unusual.

Minocycline (for chemists) @ Wikipedia  

But unusual is what often crops up on this blog. And how if one assumes that autism, sorry the autisms, are not just conditions solely pertaining to the grey-pinkish matter floating inside our skull, one starts to see how behaviour and physiology might provide some interesting perspectives. Say for example, when one starts to look at the gut microbiome...

On today's post I'm considering a few reports which recently cropped up on the research radar including the results of placebo-controlled trial of minocycline for Fragile X syndrome (FXS) published by Mary Jacena Leigh and colleagues* (open-access), a small open-trial of minocycline reported by Carlos Pardo and colleagues** (open-access) and although not autism-related, the results of a study by Parvin Ataie-Kachoie and colleagues*** (open-access) on what happened to an ovarian cancer cell line when minocycline was added, specifically with the cytokine IL-6 in mind. A bit of a mixed bag of studies by all accounts but with some potential common threads.

The Leigh study has already been covered by some media (see here) so no grand description needed from me. Suffice to say that there is a suggestion from this MIND Institute study, that minocycline might have some modest positive impact on various aspects of behaviour in paediatric cases of FXS with the requirement for further research. As per some previous chatter on this blog, this is not necessarily new news for FXS as per studies like the one by Paribello and colleagues**** (open-access). Interestingly, the Paribello results also mention something called matrix metalloproteinase-9 (MMP-9) as a particular target of minocycline which has also been discussed on this blog (see here). So, potentially (potentially!) there may be some merit in looking at minocycline for cases of FXS; although as per my blog caveat, I'm not recommending anything.

Moving on. The Pardo study (see here for the trial record), whilst small in participant numbers, looked more directly at the use of minocycline - and vitamin B6 - with ten children diagnosed with an ASD. The focus was on autism with a regressive aetiology linked to presentation, and alongside various behavioural measures, there was also analyses of various biological fluids for "markers of neuroinflammation". The study was open and unblinded so not exactly the same calibre as the Leigh trial.

The main result of the trial, er... no clinical improvements following minocycline use, even after six months of use. Indeed not only were no significant changes to behaviour reported but a variety of respiratory and gastrointestinal (GI) side-effects correlated with minocycline use. The efficacy and safety profile was not particularly great based on these study results allowing for the lack of any control group and the dosage used.

There were however, a few reported changes to some of the biochemistry under investigation, specifically with brain derived neurotrophic factor (BDNF) and hepatocyte growth factor (HGF) in mind but not in the more classically related parameters such as that MMP-9 connection. This lack of effect of minocycline on MMP-9 is slightly unusual but potentially revealing. Certainly the review by Siller & Broadie***** (open-access) hints that MMP inhibition might be a key part of the effects of minocycline in FXS. It's possible a few scenarios might pertain with regards to the biological/genetic differences between autism and FXS. One might even speculate that there is some involvement for the TIMPs (tissue inhibitors of metalloproteinases) in that non MMP inhibitory effect noted from minocycline in autism, but much more work is perhaps needed.

Indeed the authors very overtly noted that "minocycline exerted biological effects that were not translated into behavioral or neurological changes" which certainly questions the link between some of the biochemistry that was seemingly affected and presented symptoms assuming there wasn't more subtle behavioural changes.

Finally, there is the Ataie-Kachoie study on minocycline application to ovarian cancer cell lines. I'll freely admit that I know even less about cancer cell lines than I do about autism so please excuse any widely inaccurate statements that I might make. The long-and-short of it was that in the lab, minocycline seems to have an interesting effect on "the IL-6 signaling pathway" at least in ovarian cancer cells such that minocycline might reduce IL-6 or at least prevent increases after certain events. As part of my learning jounrney through this paper I did not know that IL-6 was for example being linked to cancer metastasis as discussed by Tawara and colleagues****** for example. Seemingly this metastasis might correlate with those MMPs (particularly MMP-2 and MMP-9).

I know I'm moving further and further away from my autism and FXS purpose with the Ataie-Kachoie data, but there may be some lessons to be learned. That for example minocycline might affect cases of FXS by means of impacting on MMP-9 is already under discussion. The added suggestion that minocycline might also be working on cytokines like IL-6 in an anti-inflammatory fashion is certainly another source of discussion. Indeed, I note from the Pardo autism study, that in Table 3 showing the pre- and post-treatment effects on biochemistry, the value reduction for serum IL-6 just managed to escape that magical significance point coming in at p=0.08. The change in another interesting cytokine, TNF-alpha, was even closer (p=0.074).

This has been a post comparing apples and pears to a large extent and reiterating my earlier caveat, I am by no means advocating minocycline for anything other than it's intended use with appropriate medical physician support and supervision. Outside of the discussions already included, what this post does serve to show is that (a) the actions of medicines are not necessarily restricted to what's printed on the patient information leaflet, and (b) some of those 'extra' actions might yet hold some promise for some presenting with autism or autism-like behaviours across the autisms and indeed other conditions.

To close, while recently watching the excellent film 'The Sting' I was again entranced by the piano genius of Scott Joplin's 'The Entertainer'.

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* Leigh MJ. et al. A randomized double-blind, placebo-controlled trial of minocycline in children and adolescents with Fragile X Syndrome. J Dev Behav Pediatr. 2013; 34: 147–155.

** Pardo CA. et al. A pilot open-label trial of minocycline in patients with autism and regressive features. Journal of Neurodevelopmental Disorders 2013: 5: 9.

*** Ataie-Kachoie P. et al. Minocycline suppresses Interleukine-6, its receptor system and signaling pathways and impairs migration, invasion and adhesion capacity of ovarian cancer cells: In Vitro and In Vivo studies. PLoS ONE. 2013; 8: e60817.

**** Paribello C. et al. Open-label add-on treatment trial of minocycline in fragile X syndrome. BMC Neurol. 2010; 10: 91.

***** Siller SS. & Broadie K. Matrix metalloproteinases and minocycline: therapeutic avenues for Fragile X Syndrome. Neural Plasticity. 2012; 124548.

****** Tawara K. et al. Clinical significance of interleukin (IL)-6 in cancer metastasis to bone: potential of anti-IL-6 therapies. Cancer Management & Research. 2011; 3: 177-189.

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Leigh, M., Nguyen, D., Mu, Y., Winarni, T., Schneider, A., Chechi, T., Polussa, J., Doucet, P., Tassone, F., Rivera, S., Hessl, D., & Hagerman, R. (2013). A Randomized Double-Blind, Placebo-Controlled Trial of Minocycline in Children and Adolescents with Fragile X Syndrome Journal of Developmental & Behavioral Pediatrics, 34 (3), 147-155 DOI: 10.1097/DBP.0b013e318287cd17

The focus is on autism

This is one of my more 'advertorial' posts I'm afraid, as I bring to your attention two important special supplements on autism published in two high-profile journals.

The first is yet another open-access special edition published in Nature (see link here), which complements their previous special edition from this time last year (2011). I'm impressed it has to be said, that Nature would choose to return to autism two years running, which really does tell you how much scientific and lay interest there is about the condition.

As to content, lots of interesting views and opinions but a few highlights to mention:

• Well it's nice to see that epigenetics (there's so much more to the genome) gets a mention as per this article by Sarah Williams*. The possible usefulness of systems biology is also discussed, albeit with more of slant on proteomics over my favourite, metabolomics. 
• Michael Eisenstein** talks pharmacotherapy which includes quite a bit about Fragile X syndrome chatter and all those glutamate-targeting advances (see here) which potentially offer so much. My attention however was more focused on the preliminary results from administration of N-acetlycysteine (NAC) in cases of autism and even some suggestion that the immune-inflammatory link to some cases of autism might be a target for therapy, and quite unconventional - helminthic - therapy at that. 
• Of course one cannot talk about autism nowadays with making some reference to DSM-V as per the article by Emily Singer*** which complements/is complemented by a recent piece by Jon Brock elsewhere.

The second special edition / supplement graces the journal Pediatrics, and a whole slew of articles on autism (see link here). Regular readers of this blog (hello, anyone there...) will have already been given a heads-up for one of the articles published as part of the Pediatrics supplement by a cracking group of researchers, all discussing gastrointestinal (GI) factors and autism (see here).

Some more interesting tidbits for your, pardon the pun, digestion:

• Perrin and colleagues**** discuss the use of complementary and alternative medicine (CAM) in autism. As someone who does not necessarily see dietary intervention as being anything like CAM - remember Hippocrates 'Let food be thy medicine' - it's nevertheless interesting to read about how CAM use seems to be more widespread among those children whose autism is present alongside other comorbidites such as GI problems and seizure disorders. I hate to use the term ' the bleeding obvious' but it does kinda stand to reason that GI issues might persuade someone to look at diet for example, as being a potential player to those issues. Or maybe it's just me? I note also that Dr Susan Hyman is among the authorship group to this paper, which got me wondering about the status of that gluten- and casein-free diet study that she was undertaking which still appears on the ClinicalTrials.gov website, albeit 'status unknown'. 
• Sikora and colleagues***** report some really interesting results based on what happens when ADHD and autism are comorbid. Again, probably not something completely unexpected in that quality of life is not great, or at least not as great as when ADHD symptoms are not present. If ever there was another example that comorbidity can be (a) present and (b) a real challenge for people with autism, here it is.
• Beth Malow and colleagues****** describe a potentially very informative tool, an insomnia practice pathway to help identify such issues in cases of autism. So, screening taking into account other medical factors, discussing various therapies which does not necessarily just mean introduce melatonin, and an important one here, follow-up and "evaluate effectiveness and tolerance of the therapy". It all sounds great in principle, but again I'm just going back to the 2010 Pediatrics guidance on GI conditions and autism******* and wonder how successful such best-laid plans turn out to be in practice.
• Final one, Ann Reynolds and colleagues******** talk iron and autism (as I have previously done on this blog) and report that issues with the availability of iron might not actually be all that widespread in autism after all. By saying this, I'm not taking away anything from the cases where iron availability is an issue. 

There is plenty of bedtime reading there for everyone and importantly, an ideal vehicle for keeping autism and autism research in the public consciousness. To close, a song that I think everyone would welcome, young and old, either first thing in the morning or last thing at night...

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* Williams SCP. Genetics: searching for answers. Nature. 2012; 491: S4-S6.

** Eisenstein M. Treatments: in the waiting room. Nature. 2012; 491: S14-S16.

*** Singer E. Diagnosis: redefining autism. Nature. 2012; 491: S12-S13.

**** Perrin JM. et al. Complementary and alternative medicine use in a large pediatric autism sample. Pediatrics. 2012; 130: S77-S82.

***** Sikora DM. et al. Attention-Deficit/Hyperactivity Disorder Symptoms, adaptive functioning, and quality of life in children with autism spectrum disorder. Pediatrics. 2012; 130: S91-S97.

****** Malow BA. et al. A practice pathway for the identification, evaluation, and management of insomnia in children and adolescents With autism spectrum disorders. Pediatrics. 2012; 130: S106-S124.

******* Buie T. et al. Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report. Pediatrics. 2010;125 Suppl 1:S1-18.

******** Reynolds A. et al. Iron Status in Children With Autism Spectrum Disorder. Pediatrics. 2012; 130: S154-S159.

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Endocannabinoids and fragile X syndrome

Fragile X syndrome (FXS), one of the known causes of autism or rather autistic behaviours, has been receiving quite a lot of research and media attention lately. Arbaclofen (STX209) with FXS in mind was the topic of the most recent post (see here); now we have the article by Kwang-Mook Jung and colleagues* (open-access) on endocannabinoid signalling. There may be quite a few similarities between this latest endocannabinoid research and the growing interest in glutamate and its receptors with FXS in mind, but more on that shortly.

OK let's get it out of the way. Thinking about cannabinoids, I assume some people might initially make the connection back to cannabis and the chief psychoactive substance, delta-9-tetrahydrocannabinol (Δ9-THC), associated with that (in)famous plant. Indeed with the Jung study in mind, it was perhaps inevitable that a headline like: "Cannabis chemical combats chief genetic cause of autism" complete with the necessary picture of a cannabis plant would appear (all that's missing is Bob Marley and some 'herb' music just in case readers required a little more atmosphere).

Suffice to say that the Jung paper focuses on the functioning of the endogenous (endo)cannabinoid system over and above its external chemical relation.

• In particular how in a mouse model, issues with the fragile X mental retardation protein (FMRP) associated with FXS might have some potentially important effects on endocannabinoid signalling by way of metabotropic glutamate receptor-5 (mGluR5) depression. 
• Mention is made of something called 2-arachidonoyl-sn-glycerol (2-AG), a "retrograde endocannabinoid (eCB) transmitter" but other than saying that this is one of the more abundant endocannabinoids seemingly tied into mGluR5 and related to arachidonic acid (AA), I wouldn't pretend to know much more about it. The suggestion is that loss of FMRP has knock-on effects to mGluR5-dependent release of of 2-AG.
• Aside from the basic science of endocannabinoid signalling in said mouse model of FXS, a particularly interesting part of the Jung study is the suggestion of pharmacological 'rescuing' of 2-AG signalling and the subsequent positive impact on some of the mouse subjects displayed behaviours. 
• The pharmacological agent in question was something called JZL184, an inhibitor of the enzyme which usually degrades 2-AG (monoglycerol lipase, MGL) bearing in mind that said inhibition was irreversible. 

Hopefully I've got the main features of the study and its findings right and not confused you with all the terminology. Jung et al including Daniele Piomelli are no strangers to research on the endocannabinoid system and glutamatergic signalling as per papers like this one (full-text) and this one (full-text).

There are a few very obvious caveats to this latest work; not least that mice were the lucky participants and questions on those all-important extrapolations from mice findings to human findings which still need much greater investigation outside of the range of mouse models available to autism research. Emphasising also that this was a study of fragile X syndrome and the mutations associated with this autism-presenting condition, which may not be directly transferable to the range of other non-FXS autisms.

Having said all that I'm interested in this work for a few other reasons. As mentioned earlier on, fragile X syndrome and its relationship with glutamate and glutamate signalling is fast becoming a hot topic. If I were a betting man, I'd probably put a few quid/bucks/euro on a long-shot for glutamate and its receptors turning up as a commonality in quite a few behaviourally-defined conditions. Not necessarily as a core 'reason' but an important factor nonetheless.

I note also that MGL-inhibitors such as JZL184 have been discussed with concepts like protection from neuroinflammation (as a consequence of altering prostaglandin production) in mind** and indeed with another interesting topic in mind, intestinal permeability as per this study by Alhamoruni and colleagues***. All that outside of the possible inflammatory bowel disease link**** (open-access) too. On the basis of these and other research, I'm wondering about the centrality and specificity of the brain to any effects and indeed whether maintaining 2-AG levels may also be affecting other organs as part and parcel of any therapeutic, or indeed non-therapeutic, effect.

Enough with all this science and stuff. Ladies and gentlemen, welcome to paradise...

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* Jung KM. et al. Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome. Nature Communications. 2012; 3: 1080. PMID: 23011134

** Nomura DK. et al. Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science. 2011; 334: 809-813.

*** Alhamoruni A. et al. Cannabinoids mediate opposing effects on inflammation-induced intestinal permeability. British Journal of Pharmcology. 2012; 165: 2598-2610.

**** Alhouayek M. et al. Increasing endogenous 2-arachidonoylglycerol levels counteracts colitis and related systemic inflammation. FASEB J. 2011; 25: 2711-2712.

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Kwang-Mook Jung, Marja Sepers, Christopher M. Henstridge, Olivier Lassalle, Daniela Neuhofer, Henry Martin, Melanie Ginger, Andreas Frick, Nicholas V. DiPatrizio, Ken Mackie, Istvan Katona, Daniele Piomelli, & Olivier J. Manzoni (2012). Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome Nature Communications, 3 DOI: 10.1038/ncomms2045

Kum-ba-arbaclofen

I assume quite a few people have already read the various reports about STX209* (most definitely not to be confused with ED-209) otherwise known as arbaclofen with Fragile X syndrome in mind. Hailed as 'The First Drug that Could Ease Social Withdrawal in Autism' according to one news source, the headlines are based on the results of this study by Elizabeth Berry-Kravis and colleagues** complemented by this study by Henderson and colleagues*** published on the same day in the same journal.

OK reverse please.

Seaside Therapeutics, yet another pharmaceutical company with autism or autistic behaviours in their sights, had been working for quite a while now on a new formulation, a derivative of baclofen, itself a derivative of everyone's favourite inhibitory neurotransmitter, GABA - gamma aminobutyric acid (see here for a description) as a possible therapeutic for certain behaviours associated with autism. Baclofen is normally indicated for the treatment of spasticity resulting from conditions like multiple sclerosis and cerebral palsy.

GABA is the yin to glutamate - an excitatory neurotransmitter - the yang. The balancing act between excitatory and inhibitory neurotransmitters has, on more than one occasions, been suggested to be slightly skewed in some cases of autism (and other conditions and states) as glutamate takes centre stage.

So then STX209 is, as its chemical relations are, recognised as an agonist for GABAB receptors which in turn inhibits the release of glutamate (and aspartate). You can perhaps see therefore where the interest lies.

I know quite a lot of the press around STX209 has focused on autism, but to be more accurate, Fragile X syndrome  - which presents with autistic features - is the target patient group based on the trials completed so far. The suggestion being that the primary mutation associated with Fragile X syndrome - FMR1 gene - has some knock-on effects**** including "activation of mGluR5, a metabotropic glutamate receptor". Avid watchers of the autism research landscape might remember mGluR5 as being a target for other pharmaceutics with autism/autistic characteristics in mind, including another interesting compound, GRN-529***** (at least in mice).

So:

• The recent trial of STX209** relied on human participants rather than mice, 63 of them in all, mostly male and all carrying "a full mutation in the FMR1 gene". 
• Randomised, double-blind, placebo-controlled (all the things that science really likes to hear about) was the study design and outcome-wise, the Aberrant Behavior Checklist (ABC) and the Vineland Adaptive Behaviour Scales (VABS) are listed.
• The primary endpoint of the study was a focus on irritability, which actually didn't come up trumps over placebo. 
• Having said that, there were some significant positive effects noted on areas of social avoidance in the treatment group acknowledging that the absolute number of participants in the study was relatively small and actually got even smaller following some post-hoc analysis.
• Importantly also, a few side-effects were noted, particularly in the treatment group including URTIs (13%) and headaches (8%).

I note that Seaside Therapeutics have quite recently agreed some terms over STX209 with pharmaceutical giant Roche which suggests to me that things might potentially get quite big for arbaclofen rather quickly. By saying that, I'm not in anyway endorsing the medicine. Quite a bit more data is required on long-term safety, efficacy and best responder characteristics.

With that in mind, I'll be quite interested to see the results of further trials of STX209 as are apparently planned and/or getting underway including a trial specific to children and young adults diagnosed with an autism spectrum disorders (see here). As to the mechanism of STX209 to GABAB receptors to improving social avoidance... more investigation needed I assume.

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* Hopkins CR. ACS Chemical Neuroscience Molecule Spotlight on STX209 (Arbaclofen). ACS Chem Neurosci. 2011; 2: 381.

** Berry-Kravis EM. et al. Effects of STX209 (Arbaclofen) on neurobehavioral function in children and adults with Fragile X Syndrome: a randomized, controlled, phase 2 trial. Science Translational Medicine. 2012; 4: 152ra127

*** Henderson C. Reversal of disease-related pathologies in the Fragile X mouse model by selective activation of GABAB receptors with arbaclofen. Science Translational Medicine. 2012; 4: 152ra128

**** Dölen G. et al. Correction of fragile X syndrome in mice. Neuron. 2007: 56: 955-962.

***** Silverman JL. et al. Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism. Science Translational Medicine. 2012; 4: 131ra51.

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Elizabeth M. Berry-Kravis, David Hessl, Barbara Rathmell, Peter Zarevics, Maryann Cherubini, Karen Walton-Bowen, Yi Mu, Danh V. Nguyen, Joseph Gonzalez-Heydrich, Paul P. Wang, Randall L. Carpenter, Mark F. Bear, & Randi J. Hagerman (2012). Effects of STX209 (Arbaclofen) on neurobehavioral function in children and adults with Fragile X Syndrome: a randomized, controlled, phase 2 trial Science Translational Medicine DOI: 10.1126/scitranslmed.3004214