Ambitious about Autism? All roads lead to Las Vegas


There are many odd things in the world of autism. One is ABA (Applied Behavioral Analysis), the gold standard therapy in North America, where it is seen as evidence-based.  In the rest of the world there is very little ABA and that same �evidence� is not seen as conclusive.
Raymond in Las Vegas with his �assistant� Charlie

In the US, Federal Government funded very early intensive intervention is available to anyone under three years old with an autism diagnosis. The �evidence� shows that such very early intervention can change the outcome.  But why stop at three years old? What is magical about 36 months of age? After this age some people continue to get intensive intervention and some do not; it all depends where you live and who wants to pay.
If the evidence is so strong that very early intervention is so effective, why do rich European countries leave it to far older than 36 months to even diagnose autism?
Much does not add up in the world of autism.
Personally, I am a fan of ABA as a teaching method, but only when done in a fun way, which is how our US-trained Behavioral Consultants practised it. Lots of high fives, �good jobs�, smiling faces, tickling, dancing and generally a good time; no tears and no stress.
I cannot see why you would stop your intensive intervention so soon after starting it and I really doubt you make a life-changing difference very often, by 36 months of age.
One of our Behavioral Consultants came from the New England Center for Children and I recall asking her, �so when do you stop with your therapy?� She told me that they have people in their 60s still in therapy and they might go on a trip with their assistant to Las Vegas (yes, just like in Rain Man).   
There are many special schools in the US using techniques like ABA. Because of the high ratio of staff to pupils, these schools are very expensive and somebody has to pick up the bill.
In Europe there are very few ABA schools, one of the first is called Tree House and was established in London.  It was set up by a charity called Ambitious about Autism.  This school is very expensive and the idea is that the municipal authority where you live is supposed to pay the fee for you. This would come out of their budget for special needs kids, so the more money they spend on such private schools the less money there is left over for the kids with less demanding parents, who do not advocate for their kids.
Anyway, I recently came across the fact that Ambitious about Autism has gone a step further and now runs Ambitious College for people up to the age of 25.
This made me wonder if you go to the ABA school from 4 to 18 years old and then go to the ABA college until you are 25, when does it end? Perhaps with a trip to Las Vegas? 

ABA as a treatment or a teaching method
While I see ABA as a (highly effective, in the right hands) teaching method, the ABA specialists put if forward as a proven treatment, meaning you should get better. 

Ambitious or Realistic?
When treating a three year old with autism I think you have to be ambitious, optimistic and hopeful.
At some point I think you need to be realistic.
Day care and activities for young adults with severe autism is a great idea. Including them in activities with non-autistic people would be even better.
With people living longer there are many activities for retired older people, which are entirely suitable for adults with (non-violent) severe autism, or indeed with Down Syndrome.  Why can�t the 25 year old with severe autism play table tennis with the 70 year old retired teacher and go to the same keep fit class?  Last year Monty, aged 14 with ASD, was in Shanghai and when he saw a large group of older Chinese people doing their group exercises in a public park; he joined in. Everybody enjoyed it. 
I am not sure creating a �College� for people with severe autism is helpful. Helping people with autism go to a regular college, by giving them an assistant, is a good idea.
If it really is day care, why not call it day care?
If it is about preparing for life in the real world, what was happening at the ABA school from 4 to 18 years old?



Glass Syndrome / SATB2-associated syndrome � Osteoporosis and ER�


The world�s longest glass bridge is in China.

Today�s post is about Glass Syndrome / SATB2-associated syndrome, it occurs when something goes wrong with a gene called SATB2; there are several variants because different mutations in this gene are possible.

Glass Syndrome / SATB2-associated syndrome is another of those single gene types of autism, so you can think of SATB2 as another autism gene.  As we will see in today�s post SATB2 is involved in much more than autism and is very relevant to osteoporosis and some types of cancer.

While autism caused by SATB2 is very rare, diseases in old age quite often involve the SATB2 gene being either over expressed or under expressed. As a result there is much more research on SATB2 than I expected.

The current research into Glass Syndrome / SATB2-associated syndrome is mainly collecting data on those affected, rather than investigating therapies. There are some links later in this post, for those who are interested.

The research into SATB2, unrelated to childhood developmental disorders, is much more science heavy and already contains some interesting findings.   

I have only made a shallow study, but it seems that you can reduce SATB2 expression with a drug called Phenytoin and potentially increase expression via an estrogen receptor beta agonist. We saw in earlier posts that an estrogen receptor beta agonist might well be helpful in broader autism.

As with other single gene types of autism, it will be important to look at all the downstream effects caused by a lack of SATB2, some of which will very likely overlap with what occurs in some idiopathic autism or with other single gene autisms.

In Johns Hopkins� simplification of autism into either hyper-active pro growth signaling, or hypo-active, SATB2 fits into the latter. It is associated with small heads and a small corpus callosum; that is the part that joins the left side of the brain to right side.

I think it is fair to say that SATB2 is associated with partial agenesis of the corpus callosum (ACC), a subject that has been covered in earlier posts.

I have mentioned two therapies recently that seem to help in certain variants of  ACC. The reason SATB2 causes partial agenesis of the corpus callosum (ACC) is well understood.  SATB2 needs to be expressed in the neurons that extend axons across the corpus callosum, in effect you need to build a bridge across from one side of the brain to the other and all the connections across that bridge need to match up and not be jumbled up. In some people with SATB2 they have an apparently normal corpus callosum (the bridge) but it does not work properly (the connections do not function).

SATB2 is also associated with a cleft palette, this occurs because the roof of the mouth (another bridge) does not join correctly left to right. You end up with an unwanted opening into the nose.

Building bridges is never an easy business. The Chinese have found this with their recent glass bridges, as in this post�s photo above. It looks like SATB2 is the �bridging� protein for humans, if the SATB2 gene is mutated you do not make enough of the SATB2 protein. The less SATB2 expression the more consequences there will be.

The other extreme also exists, too much SATB2 expression. That will lead to too much growth which makes it another cancer gene. In cases of aggressive prostate cancer SATB2 is over-expressed. So a therapy to slow this cancer would be to reduce SATB2 expression. For Glass Syndrome we would want the opposite. 

There is SATB2 associated syndrome research, but it is still at the stage of collecting data on people who are affected and investigating what particular mutation is present.

The logical next stage is to see more precisely the role SATB2 plays in different parts of the brain. By seeing how SATB2 interacts with the world around it, it may be possible to correct for the lack of it.  For example there is an interaction with Ctip2, a transcription factor that is necessary and sufficient for the extension of subcortical projections by cortical neurons. This look very relevant to building bridges.

Confusingly, Ctip2 is also called B-cell lymphoma/leukemia 11B encoded by the BCL11B gene. 






The research relating your bones looks the most advanced and already suggests possible therapies to both increase and reduce SATB2 expression.



The above paper (the full version is not public)  is very detailed and shows how important SATB2 may be in bone diseases and therefore be of wide clinical relevance.  It also suggests that it could be treated by gene therapy.






Molecular Regulation of SATB2 by Cytokines and Growth Factors

It appears that the anti-epileptic drug (AED) Phenytoin reduces SATB2 expression, which is the opposite of what we want, but shows that modification is possible.

Osteoporosis,  SATB2, Estrogen and ER�
There already is much in this blog about estrogen/estradiol and estrogen receptor beta. There are was a phase in this blog when there were many comments about disturbed calcium metabolism in family members.
It appears they may be connected via SATB2.
Older people lack estrogen, particularly females, and this is associated with osteoporosis.
Very recent research shows that there is an ER�-SATB2 pathway (ER� = estrogen receptor beta, which is activated by estrogen). So a reduction in estrogen during aging reduces signaling along the ER�-SATB2 pathway (making less SATB2).
We know from earlier posts that people with autism tend to have a reduced number of ER� receptors and also a lower level of estrogen/estradiol. This might explain some of the problems readers reported with bones in their family members.
This raises the question of what happens to SATB2 expression when you add a little extra estrogen/estradiol. The implication from the Chinese study highlighted later is that this may well be one way to make more SATB2 from the non-mutated copy that you have (you likely have one mutated copy and one clean copy of this gene). This is something that should be investigated.


How to treat Glass Syndrome/SATB2?
Ideally you would use gene therapy to treat Glass Syndrome/SATB2; this will in future decades very likely be possible.  In the meantime the more old-fashioned options must be relied upon.
We know that people with partial agenesis of the corpus callosum (ACC) face challenges, some of which match those faced  with Glass Syndrome/SATB2. We know certain types of ACC do respond to treatment, based on research, so it would seem highly likely that treatment for  Glass Syndrome/SATB2 should be possible.
Very likely some of the myriad of treatments researched for autism may be helpful. But which ones?
The treatment proposed by Knut Wittkowski for very early intervention in idiopathic autism to alter the trajectory from severe autism towards Asperger�s looks interesting and particularly because our reader Ling finds it helpful for her daughter with SATB2. Knut�s research identified Ponstan (mefenamic acid) as a target drug to minimize the cascade of damaging events that occurs as autism progresses in early childhood.
Here you would hope that some researcher would create a mouse model of Glass Syndrome/SATB2 and then see if Ponstan (mefenamic acid) has any effect, not to mention estradiol.


Websites with Information on Glass Syndrome/ SATB2 associated syndrome 






Some Research Relating to SATB2


Satb2 is a DNA-binding protein that regulates chromatin organization and gene expression. In the developing brain, Satb2 is expressed in cortical neurons that extend axons across the corpus callosum. To assess the role of Satb2 in neurons, we analyzed mice in which the Satb2 locus was disrupted by insertion of a LacZ gene. In mutant mice, �-galactosidase-labeled axons are absent from the corpus callosum and instead descend along the corticospinal tract. Satb2 mutant neurons acquire expression of Ctip2, a transcription factor that is necessary and sufficient for the extension of subcortical projections by cortical neurons. Conversely, ectopic expression of Satb2 in neural stem cells markedly decreases Ctip2 expression. Finally, we find that Satb2 binds directly to regulatory regions of Ctip2 and induces changes in chromatin structure. These data suggest that Satb2 functions as a repressor of Ctip2 and regulatory determinant of corticocortical connections in the developing cerebral cortex.


Striatal medium spiny neurons (MSN) are critically involved in motor control, and their degeneration is a principal component of Huntington's disease. We find that the transcription factor Ctip2 (also known as Bcl11b) is central to MSN differentiation and striatal development. Within the striatum, it is expressed by all MSN, although it is excluded from essentially all striatal interneurons. In the absence of Ctip2, MSN do not fully differentiate, as demonstrated by dramatically reduced expression of a large number of MSN markers, including DARPP-32, FOXP1, Chrm4, Reelin, MOR1 (�-opioid receptor 1), glutamate receptor 1, and Plexin-D1. Furthermore, MSN fail to aggregate into patches, resulting in severely disrupted patch-matrix organization within the striatum. Finally, heterotopic cellular aggregates invade the Ctip2-/- striatum, suggesting a failure by MSN to repel these cells in the absence of Ctip2. This is associated with abnormal dopaminergic innervation of the mutant striatum and dramatic changes in gene expression, including dysregulation of molecules involved in cellular repulsion. Together, these data indicate that Ctip2 is a critical regulator of MSN differentiation, striatal patch development, and the establishment of the cellular architecture of the striatum.







Neuroimaging. Brain abnormalities, documented in half of affected individuals who underwent head MRI, include nonspecific findings such as enlarged ventricles (12%), agenesis of the corpus callosum (5%), and prominent perivascular spaces (5%). Of interest, abnormal myelination for age and/or non-progressive white matter abnormalities appear to be particularly common (26%) in those with pathogenic nonsense, frameshift, and missense variants [Zarate & Fish 2017, Zarate et al 2017a]. Note that these findings are not sufficiently distinct to specifically suggest the diagnosis of SAS.

Other neurologic manifestations

         Hypotonia, particularly during infancy (42%)
         Clinical seizures (14%)
         EEG abnormalities without clinically recognizable seizures [Zarate et al 2017a]
         Less common neurologic issues include gait abnormalities/ataxia (17%), hypertonicity and/or spasticity (4%), and hyperreflexia (3%).



Growth restriction. Pre- and postnatal growth restriction, sometimes with associated microcephaly, can be found in individuals with SAS, particularly in those with large deletions involving SATB2 and adjacent genes (71%).

This is likely to be the most relevant paper, even though the tittle might not suggest it:-


Decline of pluripotency in bone marrow stromal cells (BMSCs) associated with estrogen deficiency leads to a bone formation defect in osteoporosis. Special AT-rich sequence binding protein 2 (SATB2) is crucial for maintaining stemness and osteogenic differentiation of BMSCs. However, whether SATB2 is involved in estrogen-deficiency associated-osteoporosis is largely unknown. In this study, we found that estrogen mediated pluripotency and senescence of BMSCs, primarily through estrogen receptor beta (ER�). BMSCs from the OVX rats displayed increased senescence and weaker SATB2 expression, stemness, and osteogenic differentiation, while estrogen could rescue these phenotypes. Inhibition of ER� or ERa confirmed that SATB2 was associated with ER� in estrogen-mediated pluripotency and senescence of BMSCs. Furthermore, estrogen mediated the upregulation of SATB2 through the induction of ER� binding to estrogen response elements (ERE) located at -488 of the SATB2 gene. SATB2 overexpression alleviated senescence and enhanced stemness and osteogenic differentiation of OVX-BMSCs. SATB2-modified BMSCs transplantation could prevent trabecular bone loss in an ovariectomized rat model. Collectively, our study revealed the role of SATB2 in stemness, senescence and osteogenesis of OVX-BMSCs. Collectively, these results indicate that estrogen prevents osteoporosis by promoting stemness and osteogenesis and inhibiting senescence of BMSCs through an ER�-SATB2 pathway.

Therefore, SATB2 is a novel anti-osteoporosis target gene.

3.2 Estrogen enhanced SATB2 levels, pluripotency and alleviated senescence of OVX-BMSCs.

Estrogen has been shown to promote bone formation and proliferation both in vivo and in vitro (Wang, J. et al., 2014; Du, Z. et al., 2015; Kim, R. Y. et al., 2015), so we asked whether estrogen affected SATB2 expression, stemness and osteogenic differentiation of BMSCs. We found that both Sham-BMSCs and OVX-BMSCs treated with 10-8M estrogen (Matsumoto, Y. et al., 2013) regained the colony forming capacity as compared to the control (Fig. 2A). Higher expression levels of SATB2, Nanog, Sox2 and Oct4, were observed in BMSCs treated with estrogen relative to the control group (Fig. 2B, C). These results were further confirmed by human BMSCs (Fig. 2D). The role of estrogen on anti-senescence was verified by the decreased SA-�-gal positive cells and alleviated expression of senescence markers (Fig. 2E, F). After osteogenic induction, the expression of osteogenic markers, Runx2 and OCN, significantly increased (Fig. 2G and H). Consistently, estrogen significantly enhanced the mineralized node formation (Fig. 2I). Interestingly, the expression of osteoclast-related activator, RANKL, and inhibitor, OPG, significantly changed in OVX-BMSCs treated with estrogen (Fig. 2J).

Together, these results suggest that estrogen rescued pluripotency and alleviated senescence of OVX-BMSCs accompanied by a higher expression of SATB2.



3.4 SATB2 is a confirmed target of ER�.  
Estrogen is known to regulate gene expression by binding to ERs, which subsequently binds to EREs present in promoters (Klinge, C. M. 2001). Analysis of 2 kb upstream and 50bp downstream of SATB2, using Promo 3.0 software, showed the presence of three putative EREs that had (achieved through site-directed mutagenesis at the ER� binding site in the SATB2 promoter). As anticipated, ER� overexpression induced by estrogen increased luciferase activity in wild-type but not mutant promoter region A (Fig. 4C, D). 
 Further, to check dynamic recruitment of ER� to the EREs following estrogen treatment, we used chromatin immunoprecipitation (CHIP). CHIP analysis was conducted in OVX-BMSCs with or without estrogen treatment using antibodies specific to ER� or IgG control. This revealed that following estrogen treatment, various putative EREs facilitated dynamic recruitment of ER�. Furthermore, the binding of ER� was considerably more robust in region A than other regions (Fig. 4E). Thus, the induction of SATB2 by estrogen is mediated by the binding of ER� to various EREs present in the SATB2 promoter.

Discussion


Although it is well-known that osteoporosis due to estrogen deficiency is associated with bone loss, the detailed mechanisms underlying this are not fully understood (Liao, L. et al., 2013; Villa, A. et al., 2015; Wang, J. et al., 2016). We recently found that the expression of SATB2 was associated with ERs, especially ER�, after estrogen treatment of BMSCs (Fig. 3A). In this study, we successfully established an ovariectomized rat model of postmenopausal osteoporosis and showed that STAB2 was associated with estrogen-ER� complex in OVX-BMSCs. Moreover, our data demonstrated that SATB2 was a downstream effector of ER�. The induction of SATB2 by estrogen was mediated by binding of ER� to various EREs present upstream of SATB2. Our study suggested the central role of SATB2 in the etiology of postmenopausal osteoporosis, suggesting it as a candidate target of osteoporosis prevention and treatment.



                                                                                                                                 


Conclusion
Our reader Ling is busy researching this syndrome and this is a good place to post comments with her findings, so others can find them later.







How much Histidine? Dermatitis and FLG mutations


Today�s post is not about autism, it is about allergy and atopic dermatitis in particular.
Many people are affected by atopic dermatitis (AD), also known as eczema; it is particularly common in those with autism. Children who develop asthma have often first developed atopic dermatitis (AD).
Atopic Dermatitis is another of those auto-immune conditions and the sooner you stabilize such conditions the better the prognosis.




Skin therapies from a company
spun-off from Manchester University


Histidine
A while back on this blog I was looking at the various amino acids and came across the observation that histidine, a precursor of histamine, appears to be a mast cell stabilizer. Mast cells are the ones that release histamine and IL-6 into your blood. Histamine then does on the trigger yet more IL-6 to be produced.  IL-6 is a particularly troublesome pro-inflammatory cytokine.
At first sight giving a precursor of histamine to people who want less histamine seems a crazy thing to do, but plenty of people report their allergies improving after taking histidine. As we have discovered, feedback loops are very important in human biology and these can be used sometimes to trick the body into doing what you want it to do. Having a higher level of histidine in your blood might make histamine production easier but it might also be telling the body not to bother, or just to delay mast cells from degranulating.  Whatever the mechanism, it does seem to work for many people. 

How Much Histidine?
Most histidine pills are 0.5g and it appears people use about 1g to minimize their allergy. 1g is the dose Monty, aged 14 with ASD, has been using during the pollen allergy season.
My sister recently highlighted a new "high tech" OTC product for skin conditions, Curapella/Pellamex, its main ingredient is histidine and it is a lot of histidine, 4g.




The company that produces the supplement have teamed up with the Universities of Edinburgh and Manchester to make a clinical trial, which is featured below.
They are considering the interaction between histidine and filaggrine (produced by the FLG gene). 

Mutations in the FLG gene are associated with atopic dermatitis and indeed with asthma, hay fever, food allergies, and, rather bizarrely, skin sensitivity to nickel.
In effect it is suggested that histidine makes filaggrine work better and thus atopic dermatitis and some other skin conditions will improve.  



Atopic dermatitis (AD), also known as eczema, is one of the most common chronic skin conditions worldwide, affecting up to 16% of children and 10% of adults. It is incurable and has significant psychosocial and economic impacts on the affected individuals. AD etiology has been linked to deficiencies in the skin barrier protein, filaggrin. In mammalian skin, l-histidine is rapidly incorporated into filaggrin. Subsequent filaggrin proteolysis releases l-histidine as an important natural moisturizing factor (NMF). In vitro studies were conducted to investigate the influence of l-histidine on filaggrin processing and barrier function in human skin-equivalent models. Our further aim was to examine the effects of daily oral l-histidine supplementation on disease severity in adult AD patients. We conducted a randomized, double-blind, placebo-controlled, crossover, nutritional supplementation pilot study to explore the effects of oral l-histidine in adult AD patients (n=24). In vitro studies demonstrated that l-histidine significantly increased both filaggrin formation and skin barrier function (P<0 .01="" respectively="" span="" style="background: yellow; margin: 0px;">Data from the clinical study indicated that once daily oral l-histidine significantly reduced (P<0 .003="" 34="" 39="" 4="" ad="" after="" and="" assessment="" by="" disease="" eczema="" measure="" of="" oriented="" patient="" physician="" scoringad="" self-assessment="" severity="" span="" the="" tool="" treatment="" using="" weeks="">. No improvement was noted with the placebo (P>0.32).The clinical effect of oral l-histidine in AD was similar to that of mid-potency topical corticosteroids and combined with its safety profile suggests that it may be a safe, nonsteroidal approach suitable for long-term use in skin conditions that are associated with filaggrin deficits such as AD. 
In this paper, we suggest that a simpler, nutritional supplementation of l-histidine may have a beneficial potential in AD.

l-histidine is a proteinogenic amino acid that is not synthesized by mammals. In human infants, it is considered �essential� due to low levels of histidine-synthesizing gut microflora and minimal carnosinase activity, which helps in releasing free l-histidine from carnosine.24 Our interest in the use of l-histidine in AD was stimulated by several observations. Firstly, in both infants and adults, a histidine-deficient diet results in an eczematous rash.25 In rodents, 3H-histidine is rapidly (1�2 hours) incorporated into profilaggrin within keratohyalin granules after intraperitoneal or intradermal injection14,26 and within 1�7 days is released as a free NMF amino acid in the upper stratum corneum.14 Furthermore, reduced stratum corneum levels of free NMF amino acids, including histidine and its acidifying metabolite urocanic acid (UCA), are associated with AD disease severity and FLG genotype.27,28

Given this evidence for the dependence of filaggrin processing and NMF formation on suitable levels of l-histidine, we hypothesized that l-histidine would both enhance filaggrin processing in an in vitro, organotypic, human skin model and have beneficial effects as a nutritional supplement in subjects with atopic dermatitis. 

After a 2-week wash-out period in which subjects were asked not to use any medicinal product for their AD, the same measures were repeated and patients were provided with identical sachets containing either 4 g l-histidine (Group A) or 4 g placebo (erythritol); Group B) which was taken once a day, dissolved in a morning fruit drink.  





Conclusion

It looks like 4g of histidine has the same potency as mild topical steroid creams, when treating atopic dermatitis.
The big problem with topical steroids is that you can only use them for a week or two. It you use them for longer, you end up with a bigger problem than the one you were trying to treat.
The 4g a day of histidine is put forward as a safe long term therapy.
Is the mode of action related to mast cells or filaggrin (FLG)? Or perhaps both?
If 1g of histidine does improve your allergies, perhaps you should feel free to try a little more.
You can buy histidine as a bulk powder. Pellamex is quite expensive, particularly if more than one family member is affected, as you would expect to find in a genetic condition.  




A RORa Agonist for Autism?


Today�s post is again about RORa, which was suggested to be a nexus where different biological dysfunctions that lead to autism may converge. I think you can consider RORa like a dimmer switch on your lights, you need to adjust the brightness to give the effect you want.



Fine tuning RORa to tune autism gene expression

I recently came across some research where the scientist clearly has the same idea. He has been working on a synthetic RORa/? agonist for some years and has investigated its use as both a cancer therapy and an autism therapy.
I have become rather interested in cancer therapies because there are so many overlaps between what can lead to cancer and what exists in autism. The big research money is of course in cancer research.
Tumor suppressor genes/proteins like PTEN and p53 have been shown to be disturbed in autism, as is Bcl-2. The Bcl-2 family of proteins regulate cell death (apoptosis); some members induce cell death and other inhibit it; the balance is important.
Generally it seems that most people with autism might benefit from more PTEN and Bcl-2. 

Autism is a developmental disorder of the nervous system associated with impaired social communication and interactions as well excessive repetitive behaviors. There are no drug therapies that directly target the pathology of this disease. The retinoic acid receptor-related orphan receptor a (RORa) is a nuclear receptor that has been demonstrated to have reduced expression in many individuals with autism spectrum disorder (ASD). Several genes that have been shown to be downregulated in individuals with ASD have also been identified as putative RORa target genes. Utilizing a synthetic RORa/? agonist, SR1078, that we identified previously, we demonstrate that treatment of BTBR mice (a model of autism) with SR1078 results in reduced repetitive behavior. Furthermore, these mice display increased expression of ASD-associated RORa target genes in both the brains of the BTBR mice and in a human neuroblastoma cell line treated with SR1078. These data suggest that pharmacological activation of RORa may be a method for treatment of autism. 
The RORs have been linked to autism in human in several studies. In 2010, Nguyen and co-workers reported that RORa protein expression was significantly reduced in the brains of autistic patients and this decrease in expression was attributed to epigenetic alterations in the RORA gene. Additional work from this group demonstrated that multiple genes associated with autism spectrum disorder are direct RORa target genes and suggested that reduction of RORa expression results in reduced expression of these genes associated with the disorder leading to the disease. Independently, Devanna and Vernes demonstrated that miR-137, a microRNA implicated in neuropsychiatric disorders, targets a number of genes associated with autism spectrum disorder including RORA. There are also additional links between RORa and autism. Deficiency of Purkinje cells is one of the most consistently identified neuroanatomical abnormalities in brains from autistic individuals, and RORa is critical in development of the Purkinje cells.- Significant circadian disruptions have also been recognized in autistic patients,- and RORs play a critical role in regulation of the circadian rhythm., Additionally, the staggerer mouse displays behaviors that are associated with autism including abnormal spatial learning, reduced exploration, limited maze patrolling, and perseverative behavior relative to wt mice.-

SR1078 is a relatively low potency compound with limited RORa efficacy (3�5 �M EC50Emax ~ 40%), but the efficacy compares favorably to other classes of compounds that have been optimized such as a 38% decrease in the same model induced by the mGluR5 allosteric modulator GRN-529 and a 47% reduction by the mGluR5 antagonist MPEP. Both of these compounds have been optimized and display high potency (single digit nanomolar range at mGluR5) and strong efficacy., Thus, we believe that focused optimization of RORa ligands will provide compounds that will have improved efficacy in this model. It should also be noted that SR1078 has both RORa and ROR? agonist activity and a RORa selective agonist has not yet been developed. Thus, it is possible that the ROR? activity of this compound may also play a role in its efficacy in this model of autism. In summary, we have demonstrated that a synthetic RORa/? agonist is able to increase the expression of key genes whose decrease in expression is associated with ASD both in cell culture and in vivo. Furthermore, the agonist decreases repetitive behavior in an animal model of autism suggesting that it is possible that ROR agonists may hold utility in treatment ASD. 

Activation of p53 function leading to cell-cycle arrest and/or apoptosis is a promising strategy for development of anti-cancer therapeutic agents. Here, we describe a novel mechanism for stabilization of p53 protein expression via activation of the orphan nuclear receptor, RORa. We demonstrate that treatment of cancer cells with a newly described synthetic ROR agonist, SR1078, leads to p53 stabilization and induction of apoptosis. These data suggest that synthetic ROR agonists may hold utility in the treatment of cancer.  

Results showed that levels of Bcl-2 decreased by 38% and 36% in autistic superior frontal and cerebellar cortices, respectively when compared to control tissues. By the same token, levels of P53 increased by 67.5% and 38% in the same brain areas in autistic subjects vs. controls respectively. Calculations of ratios of Bcl-2/P53 values also decreased by 75% and 43% in autistic frontal and cerebellar cortices vs. controls respectively. The autistic cerebellar values were significantly reduced (p < 0.08) vs. control only. There were no significant differences in levels of �-actin between the two groups. Additionally, there were no correlations between Bcl-2, P53, and �-actin concentrations vs. age or PMI in either group.
These results confirm and extend previous data that levels of Bcl-2 and P53 are altered in three important brain tissues, i.e. frontal, parietal, and cerebellar cortices of autistic subjects, alluding to deranged apoptotic mechanisms in autism.  

Conclusion
Increasing PTEN and Bcl-2 is already part of my Polypill, via the use of Atorvastatin.
There are of course many other genes miss-expressed in autism and we cannot give a drug for each one. We need to identify a handful of nexus, where multiple anomalies can be resolved with a single intervention.
It is good that Thomas Burris, the lead researcher, has been working on SR1078 for at least 6 years, let�s hope he continues to persevere.
I think it highly likely that some types of autism will need the opposite therapy, a RORa antagonist.
My method of attempting to modulate RORa will be different. I come back to my earlier gross simplification of autism :- 

As we have seen in earlier posts, the hormonal dysfunction, this time the balance between testosterone and estradiol, has a direct effect on RORa (and vice versa).



The schematic illustrates a mechanism through which the observed reduction in RORA in autistic brain may lead to increased testosterone levels through downregulation of aromatase. Through AR, testosterone negatively modulates RORA, whereas estrogen upregulates RORA through ER.

androgen receptor = AR 

estrogen receptor = ER

As you might know, many hormones are interrelated, so what are thought of as male/female sex hormones have much wider effects. They impact growth hormones and play a big role in calcium metabolism. They also affect serotonin.
We know that in most autism aromatase is reduced, estradiol is reduced and that there is reduced expression of estrogen receptor beta.
In the ideal world it might indeed be best to use an agonist or antagonist to fine tune RORa.
We have a chicken and the egg situation. Is RORa out of tune in autism because the hormones are disturbed, or vice versa?
We do know that hormones generally have feedback loops, but we also know that increasing a hormone like estradiol via obesity is not fully matched by a corresponding reduction in aromatase. So it looks highly plausible that you can tune RORa via estradiol, and that this could be a long term strategy, not just a short term strategy.
In the case of people with low T3 thyroid hormone centrally (in the brain), giving exogenous T3 may help initially, but in the long term it does not because feedback loops to the thyroid will reduce production of the pro-hormone T4. In the extreme you will make the thyroid gland shut down, this does happen to people using thyroid hormones for depression and even weight loss. 
T3 is quite commonly prescribed by alternative practitioners in the US for autism and also for depression in older people. In Europe this hormone is rarely even available. 
Many phytoestrogens are used as OTC autism therapies. These are dietary estrogens that are structurally similar to the human hormone estradiol and so produce estrogen-like effects. They include soy products, fenugreek, kudzu, EGCG etc.







Ketones and Autism Part 4 � Inflammation, Activated Microglia, CtBP, the NLRP3 Inflammasome and IL-1�

This series of posts on ketones and the ketogenic diet (KD) is nearly finished and I am glad that I made favourable comments about the KD ea...