Modulating Wnt Signaling in Autism and Cancer

Source: LDL receptor-related proteins 5 and 6 in Wnt/β-catenin signaling: Arrows point the way

In earlier posts I have covered various signaling pathways such as Wnt, mTOR and the unusually sounding Hedgehog.

You can go into huge detail if you want to understand these pathways, or just take a more superficial view. In most cases, things only start to go wrong if you are hypo/hyper (too little/too much) in these pathways.

We saw with mTOR that most people with autism are likely to have too much activity and so might benefit from mTOR inhibition, but a minority will have the opposite status and stand to benefit from more mTOR activity.

When it comes to Wnt signaling the research suggests the same situation. Wnt signaling is likely to be aberrant, but both extremes exist.

Wnt signaling networks in autism spectrum disorder and intellectual disability

Given the large volume of genetic data, analyzing each gene on its own is not a feasible approach and will take years to complete, let alone attempt to use the information to develop novel therapeutics. To make sense of independent genomic data, one approach is to determine whether multiple risk genes function in common signaling pathways that identify signaling “hubs” where risk genes converge. This approach has led to multiple pathways being implicated, such as synaptic signaling, chromatin remodeling, alternative splicing, and protein translation, among many others. In this review, we analyze recent and historical evidence indicating that multiple risk genes, including genes denoted as high-confidence and likely causal, are part of the Wingless (Wnt signaling) pathway. In the brain, Wnt signaling is an evolutionarily conserved pathway that plays an instrumental role in developing neural circuits and adult brain function.

While the human genetic data is an important supporting factor, it is not the only one. There are a number of mouse genetic knockout (KO) models targeting Wnt signaling molecules, describing molecular, cellular, electrophysiological, and behavioral deficits that are consistent with ASD and ID. Furthermore, the genes involved in Wnt signaling are of significant clinical interest because there are a variety of approved drugs that either inhibit or stimulate this pathway.

There are many drugs developed and tested as modulators of Wnt signaling in the cancer field that could potentially be repurposed for developmental cognitive disorders. In cases where a reduction in Wnt signaling is thought to underlie the pathology of the disorder, usage of compounds that elevated canonical Wnt signaling could be applied. An example of this is GSK-3β inhibitors that have failed in cancer trials but may be effective for ASDs and ID (e.g., Tideglusig, ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT02586935","term_id":"NCT02586935"}}NCT02586935). In cases where elevated Wnt signaling is thought to contribute to disease pathology, there are many potential options to inhibit canonical Wnt signaling using chemicals (Fig. 1) that inhibit the interaction between β-catenin and its targets (e.g., inhibiting β-catenin interaction with the TCF factors), disheveled inhibitors (through targeting of the PDZ domain which generally inhibit the Frizzled–PDZ interaction), and tankyrase inhibitors (e.g., XAV939, which induces the stabilization of axin by inhibiting the poly (ADP)-ribosylating enzymes tankyrase 1 and tankyrase 2)

As autism candidates emerge, cancer pathway rises to top

In recent years, strong autism ties have cropped up for one group of genes in particular: those that make up a well-known signaling pathway called WNT, which also has strong links to cancer. This pathway is especially compelling because some people with autism carry mutations in various members of it, including one of its central players: beta-catenin¹. What’s more, studies from the past year indicate that several of the strongest autism candidate genes, including CHD8 and PTEN, interact with this pathway.

“There might be a particular subgroup of genes associated with autism that could all be feeding into or be regulating this pathway,” says Albert Basson, reader in developmental and stem cell biology at King’s College London, who studies CHD8 and WNT. “That clearly has emerged as a relatively major theme over the last few years.”

The connection between cancer and some autism is over-activated pro-growth signaling pathways. Many signaling pathways have growth at one extreme and cell death at the other. In cancer you actually want cell death to suppress tumor growth; in much autism there is also too much growth.  

Many cancers are associated with elevated signaling of mTOR, Wnt and indeed Hedgehog.  These are targets for cancer drug therapy and so there is already a great deal known.

A complication is that in a developmental neurological condition, like autism, it also matters when these signaling pathways were/are disturbed. For example Wnt signaling is known to play a role in dendritic spines and synaptic pruning, some of this is an ongoing process but other parts are competed at an early age, so it would matter when you intervene to modulate these pathways.

Historically cancer therapies involve potent drugs, often with potent side effects, however in recent years there has been growing awareness that some safe existing drugs can have equally potent anti-cancer effects. Many of these drugs are anti-parasite drugs, but even the very widely used diabetes drug Metformin has been shown to have significant anti-cancer effects, not to forget Simvastatin.

Many autism pathways/genes play a role in cancer (RAS, PTEN) and the upstream targets considered in cancer research are also autism targets.  For example many human cancers are RAS dependent and in theory could be treated by a RAS inhibitor, but after decades of looking nobody has found one. So instead scientists go upstream to find another target that will indirectly reduce RAS. This led to the development of PAK1 inhibitors that will reduce RAS.

RAS plays a role in some types of intellectual disability and indeed autism. The collective term is RASopathy.  Logically, drugs that modulate RAS to treat cancer might be helpful in modulating RAS for some autism.

Most types of cancers are complex and so there are multiple potential targets to attack them, but also the same target can have multiple possible approaches. RAS dependent cancers can be targeted via Wnt and even Hedgehog signaling.

This may sound all very complicated but does it have any relevance to autism?

It apparently does because almost all these pathways are known to be disturbed hypo/hyper in autism.  This means that clever insights developed for cancer can be repurposed for autism.

Anti-parasite drugs and Cancer

It is indeed remarkable how many anti-parasite drugs have an anticancer effect and indeed there is a much maligned theory to justify this.

Clinical Evaluation of a New Form of Cancer Therapy Based on the Principles of Atavistic Metamorphosis

Quite possibly it is just a coincidence.

There are many ways to kill parasites, one of which involves starving them of ATP. ATP is the fuel that is produced in your mitochondria.

Cancer cells and many parasites use a very inefficient way to produce ATP that does not require oxygen. In normal human cells the process followed is known as OXPHOS, by which glucose and oxygen from the blood is converted into ATP (energy) is very efficient. Only when you run low on oxygen, like a marathon runner at the end of the race, can you run into trouble because there is not enough oxygen for OXPHOS.  What happens next is anaerobic respiration, when a different process takes over to make ATP. It is much less efficient and causes lactic acidosis which makes marathon runners' muscles hurt.

A cheap anti-parasite drug Pyrvinium targets anaerobic respiration and starves the parasite of ATP and thus kills it. Another common children’s anti-parasite drug albendazole also works by starving the parasite of ATP.

Other anti-parasite drugs work in different ways.

We already know from the autism trials of Suramin, another anti-parasite drug,  that it works via P2X and P2Y purinergic channels.

Ivermectin  binds to glutamate-gated chloride channels (GluCls) in the membranes of invertebrate nerve and muscle cells, causing increased permeability to chloride ions, resulting in cellular hyper-polarization, followed by paralysis and death.  Fortunately in mammals ivermectin does not cross the BBB.

Ivermectin is also a PAK1 inhibitor and a positive allosteric modulator of P2X7.

Both PAK1 and P2X7 are relevant to many cancers and so not surprisingly research shows that Ivermectin has an anti-cancer effect.

Ivermectin appears to have a positive effect in some autism, but strangely it does not cross the BBB.

Mebendazole is another extremely cheap children’s anti-parasite drug which has remarkable potential anti-cancer properties. It inhibits hedgehog signaling and, via the inhibition of TNIK, it is a Wnt inhibitor.

Unfortunately in the US the private sector has also noticed the anticancer effects of Mebendazole and albendazole and they have recently become astronomically expensive. Mebendazole (MBZ), which costs almost nothing in many countries, now costs hundreds of dollar per dose in the US under the name Emverm. Outside of the US, Mebendazole is OTC in many developed countries. In poor countries it is donated free by big pharma.

In the cancer research they consider taking advantage of the fact that cimetidine (a cheap H2 antihistamine) interacts with Mebendazole to increase its bioavailability. Cimetidine is by chance another generic drug also being considered to be repurposed for cancer.

While some anti-parasite drugs like Suramin have side effects or cannot be taken regularly like Ivermectin, others are seen as safe for continued use even at high doses (e.g. Mebendazole and albendazole).  

Anti-parasite drugs and Autism

Just as many anti-parasite drugs seem to have a positive effect on some cancers it looks likely that the same may be true for autism.  This does not mean that parasites cause either cancer or autism.

We know from Professor Naviaux that some people respond to Suramin.

Two people who comment on this blog have found their child responds to PAK1 inhibitors, one of which is the drug Ivermectin.

There are groups of people on the internet who think parasites cause autism and you will find some of them if you google “autism mebendazole”, but there are some very valid reasons why some people’s autism may respond to mebendazole, but nothing to do with little worms.

Potency of Anticancer drugs

Failed anticancer drugs are already considered as possible drugs to treat neurological conditions.

The same pathways do seem to be involved in some cancer and some neurological conditions, but the severity by which that pathway is affected may be very different, so a new drug may lack potency to treat a type of cancer but be potent enough to benefit others.

In the case of the anti-parasite drugs Ivermectin and indeed mebendazole the dosage being used in current cancer studies are very much higher than normally used.

Very little mebendazole makes its way out of your intestines and so researchers counter this by using a dose 15 times higher and even taking advantage of the interaction with the H2 antagonist cimetidine to boost bioavailability.

The standard human dose of Ivermectin is 3mg, but in the cancer trials (IVINCA trial - IVermectin IN CAncer) in Switzerland and Spain the trial dose is 12, 30 and 60 mg.

So when it comes to autism and the possible repurposing of these drugs, the cancer studies will give valuable safety information, but the likely dose required to fine-tune these signaling pathways will likely be a tiny fraction of the cancer dose.

The newly developed cancer drugs that fail in clinical trials, may have potential in autism but it is unlikely that anyone will develop them, test them and bring them to the market.

The clever thing for autism seems to be to keep an eye on the existing generic drugs considered to benefit the overlapping cancer pathways.

Conclusion

Aberrant Wnt signaling has been identified by researchers as playing a key role in autism; the Simons Foundation is among those now funding further research.

In practical terms you can be either hypo or hyper, but hyper seems more likely. It may be a case of shutting the stable door after the horse has bolted, because the ideal time to modulate Wnt signaling is probably as a baby, or before. Nonetheless some older people may indeed benefit from modulating Wnt; the Simons Foundation must also believe so.

In the case of people with hyperactive Wnt signaling, there is a case to make for the potential use of the cheap anti-parasite drug Mebendazole.

The drug Mebendazole (MBZ) can found in three states/polymorphs called Polymorph A, B or C. This is relevant because they do not cross the blood brain barrier to the same extent.

Brain Penetration and Efficacy of Different Mebendazole Polymorphs in a Mouse Brain Tumor Model  

To treat brain tumors, or indeed potentially some autism, you need MBZ-B or MBZ-C, it looks like MBZ-A does not cross the blood brain barrier.

Fortunately, MBZ-C is  the polymorph found most commonly in generic mebendazole tablets.  

Ivermectin is known not to cross the blood brain barrier but yet has been shown to show anti-tumor activity in brain cancer. The anti-cancer effect is thought to be as a PAK1 inhibitor, but this effect must be occurring outside the brain. Some people do use Ivermectin for autism.

The people using Ivermectin for autism are told they cannot use it continuously. Perhaps as the high dose cancer trials evolve the safety advice may change.

Suramin, the Purinome and Autism

Purinergic signaling is one way cells communicate with each other.  It is still an emerging area of science and medicine.

The home of Cell Danger Response and

Anti-Purinergic Therapy

Purinergic signaling is an important regulatory mechanism in a wide range of inflammatory diseases. Shifting the balance between purinergic P1 and P2 signaling is an emerging therapeutic concept that aims to dampen inflammation and promote healing.  This has some similarity with shifting the balance between th1, th2 and th17 in the immune response.

Purinergic signaling plays a role in the nervous system, the immune system and the endocrine system, all implicated in autism. It is one way that microglia in the brain can be activated, which is a common feature of autism.

Robert Naviaux

Robert Naviaux, an autism researcher, believes that
the purinergic signaling complex of a cell, sometimes known as the purinome, lies behind some types of autism. He is researching the use of an old anti-parasite drug called Suramin to treat autism.  Having started on mouse models of autism he has moved on to humans and has been encouraged by his initial findings.

Naviaux promotes his idea of the Cell Danger Response (CDR) a metabolic response to a threat, which encompasses inflammation, innate immunity, oxidative stress, and the ER (Endoplasmic Reticulum) stress response.

The CDR is maintained by purinergic signaling and it seems that in some types of disease this signaling remains active. Inhibiting purigenic signaling is put forward as a therapy for some chronic disorders.

Naviaux proposes his Anti-Purinergic Therapy (APT) to correct multiple metabolic anomalies that were produced by an over- activated Cell Danger Response (CDR).  In his mouse experiments his therapy did indeed correct multiple metabolic anomalies.

When researching Anti-PurinergicTherapy (APT) and Cell Danger Response (CDR) it is hard to find anything written by anyone other than Naviaux and his team.  This is not necessarily a bad thing, but given all Naviaux’s papers it does look odd.

My conclusion is that Naviaux may well be proven correct, but for now his ideas are still outside the mainstream.

Naviaux’s initial idea seems to have been to prove that APT works in autism using an existing drug (Suramin) and then afterwards develop a new, safer drug. Over time the view has shifted towards thinking that the existing drug, suramin, is safe enough.


Suramin

Suramin has existed as a drug for a hundred years.  It is used to treat used to treat African sleeping sickness and river blindness, which are caused by parasites.

In parasites Suramin is effective by inhibiting their energy metabolism and thus killing them.

A drawback with Suramin is that it has to been injected intravenously and, as with many anti-parasitic drugs, it cannot be taken often. In people with a parasite infection there can be toxicity, but in people without such an infection, the drug is now considered safe below the level of 200 μM. It reacts very little with other drugs.

Fortunately Suramin has a long half-life, usually found to be about two months, but Naviaux found it to be just two weeks in his human trial.  The longer the half-life the less often you would have to take  Suramin. I wonder if his very small initial dose has affected the half-life, which should not be the case; but there must be a reason.



Naviaux’s antipurinergic therapy research history

1.     Maternal immune activation mouse model of autism (2013)

2.     Fragile X mouse model (2014/5)

3.     Human stage 1 trial with single dose Suramin (2015/17)

Antipurinergic Therapy Corrects the Autism-Like Features in the Poly(IC) Mouse Model

Autism spectrum disorders (ASDs) are caused by both genetic and environmental factors. Mitochondria act to connect genes and environment by regulating gene-encoded metabolic networks according to changes in the chemistry of the cell and its environment. Mitochondrial ATP and other metabolites are mitokines—signaling molecules made in mitochondria—that undergo regulated release from cells to communicate cellular health and danger to neighboring cells via purinergic signaling. The role of purinergic signaling has not yet been explored in autism spectrum disorders. 

Objectives and Methods

We used the maternal immune activation (MIA) mouse model of gestational poly(IC) exposure and treatment with the non-selective purinergic antagonist suramin to test the role of purinergic signaling in C57BL/6J mice. 

Results

We found that antipurinergic therapy (APT) corrected 16 multisystem abnormalities that defined the ASD-like phenotype in this model. These included correction of the core social deficits and sensorimotor coordination abnormalities, prevention of cerebellar Purkinje cell loss, correction of the ultrastructural synaptic dysmorphology, and correction of the hypothermia, metabolic, mitochondrial, P2Y2 and P2X7 purinergic receptor expression, and ERK1/2 and CAMKII signal transduction abnormalities. 

Conclusions

Hyperpurinergia is a fundamental and treatable feature of the multisystem abnormalities in the poly(IC) mouse model of autism spectrum disorders. Antipurinergic therapy provides a new tool for refining current concepts of pathogenesis in autism and related spectrum disorders, and represents a fresh path forward for new drug development.

  

Antipurinergic therapy corrects the autism-like features in the Fragile X (Fmr1knockout) mouse model

Background

This study was designed to test a new approach to drug treatment of autism spectrum disorders (ASDs) in the Fragile X (Fmr1) knockout mouse model.

Methods

We used behavioral analysis, mass spectrometry, metabolomics, electron microscopy, and western analysis to test the hypothesis that the disturbances in social behavior, novelty preference, metabolism, and synapse structure are treatable with antipurinergic therapy (APT).

Results

Weekly treatment with the purinergic antagonist suramin (20 mg/kg intraperitoneally), started at 9 weeks of age, restored normal social behavior, and improved metabolism, and brain synaptosomal structure. Abnormalities in synaptosomal glutamate, endocannabinoid, purinergic, and IP3 receptor expression, complement C1q, TDP43, and amyloid β precursor protein (APP) were corrected. Comprehensive metabolomic analysis identified 20 biochemical pathways associated with symptom improvements. Seventeen pathways were shared with human ASD, and 11 were shared with the maternal immune activation (MIA) model of ASD. These metabolic pathways were previously identified as functionally related mediators of the evolutionarily conserved cell danger response (CDR).

Conclusions

The data show that antipurinergic therapy improves the multisystem, ASD-like features of both the environmental MIA, and the genetic Fragile X models. These abnormalities appeared to be traceable to mitochondria and regulated by purinergic signaling.

Clinical Trial Launched to Assess Safety and Efficacy of Autism Drug Treatment 

Researchers at the University of California, San Diego School of Medicine have launched a clinical trial to investigate the safety and efficacy of an unprecedented drug therapy for autism.

The phase 1 clinical trial, which is recruiting 20 qualifying participants, will evaluate suramin – a century-old drug still used for African sleeping sickness – as a novel treatment for children with a diagnosis of Autism Spectrum Disorder (ASD). Previous published research by Robert K. Naviaux, MD, PhD, professor of medicine, pediatrics and pathology at UC San Diego School of Medicine, and colleagues reported that a single injection of suramin reversed symptoms of ASD in mouse models.

This trial is the first to test suramin in children with ASD.

In the trial, suramin will be given as a single dose through an intravenous line. Half of the participating children will receive suramin; half will receive a placebo (saline infusion). Behavioral and medical tests will be conducted before and after treatment, and include some blood and urine analyses.

The trial is the first clinical investigation of a novel theory, advanced by Naviaux, that posits autism may be a consequence of abnormal cell communication resulting from abnormal activation of the cell danger response.

Cells threatened or damaged by microbes, such as viruses or bacteria, or by physical forces or by chemicals, such as pollutants, react defensively, a part of the normal immune response, Naviaux said. Their membranes stiffen. Internal metabolic processes are altered – most notably mitochondria, the cells’ critical “power plants” – resulting in activation of the cell danger response and reduced communications between cells.

Naviaux said the cell danger response theory does not contradict other research regarding the causes of autism. Rather, it offers another perspective and, perhaps, a new therapeutic target.

Because suramin treatment for autism is unprecedented, Naviaux emphasized it is not known whether the drug will produce any beneficial effect in humans. He noted that suramin, as currently constituted, cannot be used for more than a few months without a risk of toxicity in humans and that it is not available as an ongoing treatment. 

NEWSLETTER—The UCSD Suramin Autism Study


The 2017 Clinical Trial


I think the interviews with parents and press release from the University are actually a better read than the clinical trial and gives a different impression.



Interviews with Parents (click)



Press Release:-


Researchers Studying Century-Old Drug in Potential New Approach to Autism


Five of the 10 boys received a single, intravenous infusion of suramin, a drug originally developed in 1916 to treat trypanosomiasis (sleeping sickness) and river blindness, both caused by parasites. The other five boys received a placebo. The trial followed earlier testing in a mouse model of autism in which a single dose of suramin temporarily reversed symptoms of the neurological disorder.

Participating families also reported benefits among the children who received suramin. “We saw improvements in our son after suramin that we have never seen before,” said the parent of a 14-year-old who had not spoken a complete sentence in 12 years.

“Within an hour after the infusion, he started to make more eye contact with the doctor and nurses in the room. There was a new calmness at times, but also more emotion at other times. He started to show an interest in playing hide-and-seek with his 16-year-old brother. He started practicing making new sounds around the house. He started seeking out his dad more.
“We have tried every new treatment out there for over 10 years. Nothing has come close to all the changes in language and social interaction and new interests that we saw after suramin. We saw our son advance almost three years in development in just six weeks.”

“We had four non-verbal children in the study,” said Naviaux, “two 6-year-olds and two 14-year-olds. The six-year-old and the 14-year-old who received suramin said the first sentences of their lives about one week after the single suramin infusion. This did not happen in any of the children given the placebo.”

Additionally, Naviaux said, “that during the time the children were on suramin, benefit from all their usual therapies and enrichment programs increased dramatically. Once suramin removed the roadblocks to development, the benefit from speech therapy, occupational therapy, applied behavioral analysis and even from playing games with other children during recess at school skyrocketed. Suramin was synergistic with their other therapies.”
Naviaux and colleagues do not believe CDR is the cause of ASD, but rather a fundamental driver that combines with other factors, such as genetics or environmental toxins. And suramin, at this stage, is not the ultimate answer.

But the therapeutic benefit of suramin was temporary: Improvements in the treated boys’ cognitive functions and behaviors peaked and then gradually faded after several weeks as the single dose of suramin wore off.

The primary import of the trial’s findings, said Naviaux, is that it points a way forward, that suramin should be tested in larger, more diverse cohorts of persons with ASD. (Naviaux said his research has been limited by costs; his lab is primarily supported through philanthropy.)
“This work is new and this type of clinical trial is expensive,” he said. “We did not have enough funding to do a larger study. And even with the funding we were able to raise, we had to go $500,000 in debt to complete the trial.”

But “even if suramin itself is not the best antipurinergic drug for autism, our studies have helped blaze the trail for the development of new antipurinergic drugs that might be even better,” said Naviaux. “Before our work, no one knew that purinergic signaling abnormalities were a part of autism. Now we do, and new drugs can be developed rationally and systematically.”

Levitt at USC agreed: “The suramin pilot study is too small from which to draw specific conclusions about the treatment, but there is no doubt that the pilot study reports positive outcomes for all five children who received the medication. The findings provide a strong rationale for developing a larger study that can probe functional improvements in children in greater depth.”

The potential financial cost of ASD treatment using suramin cannot yet be determined for several reasons, the study authors said. First, additional trials are required to determine the effective dosage and frequency for different types of patients. Suramin is used much differently for treating sleeping sickness, but the cost for a one month course of treatment is modest: approximately $27.

Study:-

Low-dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial

Objective: No drug is yet approved to treat the core symptoms of autism spectrum
disorder (ASD). Low-dose suramin was effective in the maternal immune
activation and Fragile X mouse models of ASD. The Suramin Autism Treatment-
1 (SAT-1) trial was a double-blind, placebo-controlled, translational pilot
study to examine the safety and activity of low-dose suramin in children with
ASD. Methods: Ten male subjects with ASD, ages 5–14 years, were matched by
age, IQ, and autism severity into five pairs, then randomized to receive a single,
intravenous infusion of suramin (20 mg/kg) or saline. The primary outcomes
were ADOS-2 comparison scores and Expressive One-Word Picture Vocabulary
Test (EOWPVT). Secondary outcomes were the aberrant behavior checklist,
autism treatment evaluation checklist, repetitive behavior questionnaire, and
clinical global impression questionnaire. Results: Blood levels of suramin were
12 1.5 lmol/L (mean SD) at 2 days and 1.5 0.5 lmol/L after 6 weeks.
The terminal half-life was 14.7 0.7 days. A self-limited, asymptomatic rash
was seen, but there were no serious adverse events. ADOS-2 comparison scores
improved by 1.6 0.55 points (n = 5; 95% CI = 2.3 to 0.9; Cohen’s
d = 2.9; P = 0.0028) in the suramin group and did not change in the placebo
group. EOWPVT scores did not change. Secondary outcomes also showed
improvements in language, social interaction, and decreased restricted or repetitive
behaviors. Interpretation: The safety and activity of low-dose suramin
showed promise as a novel approach to treatment of ASD in this small study.

Click read to read the full Q&A 

Reviews of the trial published in 2017

Many people had great expectations from this trial.  As expected, Naviaux goes into huge detail analyzing his biological markers. 

Unfortunately the sample is just too small; only 5 people received the single dose treatment. I am sure they would have had no shortage of volunteers and the study would have had far more value with 50 people receiving the drug.

They will tell you the trial cost many hundreds of thousands of dollars.  How much more to include a few more participants?

Since all autism trials use different methods to measure the severity of autism we cannot compare the potency of its effect to say the last bumetanide trial.

Researchers should be told by the FDA/EMA to use at least one rating scale in common with other studies.

The big surprise for me was the short half-life of just 14 days. The drug is usually quoted as having a half life three times longer. 

The next stage will hopefully have more participants and compare the effect of multiple doses of increasing amount.

Please Dr Naviaux, use CARS (Childhood Autism Rating Scale), include children with epilepsy, GI problems, asthma etc.  Have a balance between early onset autism, regressive autism and of course severity of autism.

Parental reporting of improvements, while important, is hugely open to bias. All the kids that received Suramin developed a rash on their body and none of the placebo group did, so I guess the parents who saw the rash would have built up their hopes.

Nonetheless the trial did show a short term benefit from Suramin.  But is it a NAC type of benefit, or a bumetanide scale of benefit?



Reviews of Naviaux

When researching Anti-PurinergicTherapy (APT) and his Cell Danger Response (CDR) it is hard to find anything written by anyone other than Naviaux.

There is this review of his findings:-

Antipurinergic Therapy with Suramin as a Treatment for Autism Spectrum Disorder

Naviaux is clearly highly intelligent and if you read his papers it is clear he has an unusually broad knowledge of autism.  His approach of validating his ideas in multiple types of mouse model (MIA and fragile-X) and then moving on to humans, is correct.

Naviaux is also an expert in mitochondrial disease. 



Anti-purinergic Therapy and Chronic Fatigue Syndrome

One problem with neurological conditions like fibromyalgia, Chronic Fatigue Syndrome and sometimes even MS (Multiple Sclerosis) is that people do not think they are real conditions, or that sufferers exaggerate their symptoms.

Many alternative practitioners who aim to treat these conditions also treat people with autism.


Naviaux suggests that Chronic Fatigue Syndrome is an objective metabolic disorder that could also respond to antipurinergic therapy.

Naviaux may indeed be correct, but I am not sure it helps establish the credibility of his therapy for autism. 

Metabolic Features of Chronic Fatigue Syndrome (CFS)

The chemical signature that we discovered is evidence that CFS is an objective metabolic disorder that affects mitochondrial energy metabolism, immune function, GI function, the microbiome, the autonomic nervous system, neuroendocrine, and other brain functions. These 7 systems are all connected in a network that is in constant communication using the language of chemistry and metabolism.

All animals have ways of responding to changes in environmental conditions that threaten survival. We discovered that there is a remarkable uniformity to this cellular response regardless of the many triggers that can produce it. We have used the term, the cell danger response (CDR) to describe the chemical features that underlie this response. Historical changes in the seasonal availability of calories, microbial pathogens, water stress, and other environmental stresses have ensured that we all have inherited hundreds to thousands of genes that our ancestors used to survive all of these conditions.

The body responds differently to the absence of resources (eg, caloric restriction or famine) than to the presence of pathogens and toxins.  We can classify two responses: a single-step response to the absence of resources, and a two-step process in response to the presence of a threat.  Both responses are completed by a return to normal.

When resources are severely curtailed or absent, metabolism is decreased to conserve limited resources in an effort to “outlive” the famine. This is often called a caloric restriction response. On the other hand, when the cell is faced with an active viral, bacterial, or fungal attack, or certain kinds of parasitic infection, or severe physical trauma this activates the two-step response.  The first step is to acutely activate the CDR. Innate immunity and inflammation are regulated by the metabolic features of the CDR. Activation of the CDR sets in motion a powerful sequence of reactions that are tightly choreographed to fight the threat. These are tailored to defend the cell against either intracellular or extracellular pathogens, kill and remove the pathogen, circumscribe and repair the damage, remember the encounter by metabolic and immunologic memory, shut down the CDR, and to heal.

In most cases, this strategy is effective and normal metabolism is restored after a few days or weeks of illness, and recovery is complete after a few weeks or months.

However, if the CDR remains chronically active in either state, many kinds of chronic complex, chronic diseases can occur. In the case of CFS, when the CDR gets stuck, or is unable to overcome a danger, the body enters into a kind of siege metabolism that further diverts resources away from mitochondria and sequesters or jettisons key metabolites and cofactors to make them unavailable to an invading pathogen. This has the effect of further consolidating the hypometabolic state. When the hypometabolic response to threat persists for more than 6 months, it can cause CFS and lead to chronic pain and disability. Metabolomics now gives us a way to characterize this response objectively, and a way to follow the chemical response to new treatments in systematic clinical trials.

Suramin Pharmacology

Suramin has a broad effect blocking receptors both P2X and P2Y, it does not have an effect on the third type of purinergic receptors called P1.

If you believe in the idea of balancing P1 and P2 signaling, you might consider increasing the effect of the P1 receptors to counteract excessive signaling from P2.  I am not sure I agree with this because P1 agonists would make asthma worse, not better.  Unless the idea is to counter excess P2 signaling, by reducing P1 signaling. P1 antagonists (that reduce P1 signaling) include theophylline which I did suggest for other reasons might help some autism.

If you want to be an early adopter of the Dr Naviaux, you need a P2 antagonist.

Suramin is not expensive, but rarely used in developed countries.

Source: https://www.biotrend.com/download/NetBTReview3-9-2008.pdf

Conclusion 

I think that Suramin is an interesting therapy, even if not everybody is convinced at the proposed mode of action. It does help both in mouse models of autism and in a very small human trial. We now need a large trial that includes a better behavioral assessment of the result, so we can actually judge it properly.

Will it help everybody with an autism diagnosis? I doubt it, but then I do not think any single drug ever will.

The question is more are there any biomarkers for who might respond and Naviaux does mention the “fever effect”.

I think the more people consider the broader metabolic symptoms, the easier it will become to put people into sub-groups of autism and assign them effective therapies.

As with Bumetanide, which is effective in a something like 40% of autism, I expect Suramin will be partially effective and will need other therapies to be added.

A very important point is the cost of clinical trials and indeed drug approval in the US. If just the overspend on this trial was  $500,000, a trial on 10 kids with a single infusion of the trial drug, it is time to move the research to India or Eastern Europe.

North Korea will develop a ballistic missile with nuclear warheads for less money than it costs to develop a drug in the US. 

Why do you think Bumetanide is not being developed as an autism therapy in the US?  It costs too much.

Tangeretin vs Ibuprofen, as PPARγ agonists for Autism. What about PPARγ for Epilepsy?

Summary of the therapeutic actions of PPARγ in diabetic nephropathy

From:  Peroxisome proliferator-activated receptors and renal diseases

I did write an earlier post about NSAIDs (Nonsteroidal anti-inflammatory drugs) like Ibuprofen, which I expected to have no effect on autism.

  

Cytokines from the Eruption of Permanent Teeth causing Flare-ups in Autism

However, to my surprise, I found that certain types of autism “flare-up” do respond very well to Ibuprofen.  Based on the comments I received, it seems that many other people have the same experience.

NSAIDs work by inhibiting something called COX-2, but they also inhibit COX-1.  The side effects of NSAIDs come from their unwanted effect on COX-1.

NSAIDs are both pain relievers and, in high doses, anti-inflammatory.  Long term use of NSAIDs is not recommended, due to their (COX-1 related) side effects.

Observational Study

All I can say is that in Monty, aged 11 with ASD, and with his last four milk teeth wobbly but refusing to come out, the increase in the cytokine IL-6 that the body uses to signal the roots of the milk teeth to dissolve seems to account for some of his flare-ups.  I do not think it is anything to do with pain.

This is fully treatable with occasional use of Ibuprofen and then “extreme behaviours” are entirely avoided.

Sytrinol (Tangeretin) vs Ibuprofen

Since Ibuprofen, when given long term, has known problems, I looked for something else.

On my list of things to investigate has been “selective PPAR gamma agonists”, which is quite a mouthful.  The full name is even longer.  The nuclear transcription factor peroxisome proliferator activated receptor gamma (PPARy) regulates genes in anti-inflammatory, anti-oxidant and mitochondrial pathways.  All three of these pathways are affected in autism.

We already know that non-selective PPARy agonists, like pioglitazone, developed to treat type 2 diabetes, can be used to treat autism.  The problem is that being “non-selective” they can have nasty side effects, leading to Pioglitazone being withdrawn in some markets.

  

Effect of pioglitazone treatment on behavioral symptoms in autistic children

  

While looking for a “better” PPARγ agonist, I came across the flavonoid Tangeretin, which is commercially available in a formulation called Sytrinol.

An effective PPARγ agonist would have many measurable effects.  The literature is full of natural substances that may, to some degree, be PPARγ agonists, but you might have to consume them by the bucket load to have any effect.

The attraction of Sytrinol is that it does have a measurable effect in realistic doses.  Sytrinol is sold as a product to lower cholesterol.  Tangeretin is a PPARγ agonist and you would expect a PPARγ agonist to improve insulin sensitivity and also reduce cholesterol. There are clinical trials showing this effect of Sytrinol.

Sytrinol (Tangeretin) Experiment

The most measurable effect of using Sytrinol for six weeks is that we no longer need any Ibuprofen.  It is measurable, since I am no longer needing to buy Ibuprofen any more.

About three days a week Monty’s assistant would need to give him Ibuprofen at school.  This all stopped, even though occasional complaints about wobbly teeth continue.

Nobody markets  Sytrinol (Tangeretin) as a painkiller.

Note:- Sytrinol capsules contain a blend of 270mg PMF (polymethoxylated flavones, consisting largely of tangeretin and nobiletin) + 30mg tocotrienols. Nobiletin is closely related to tangeretin, while tocotrienols are members of the vitamin E family.  All three should be good for you.

Tangeretin and Ibuprofen are both PPARγ agonists

The explanation for all this may indeed be that Tangeretin and Ibuprofen are both PPARγ agonists.  Inhibiting COX-2 may have been irrelevant.

Peroxisome Proliferator-activated Receptors α and γ Are Activated by Indomethacin andOther Non-steroidal Anti-inflammatory Drugs

  

It may be that by regulating the anti-inflammatory genes, via  PPARγ, the Sytrinol has countered the “flare-up” caused by the spike in IL-6.

Anyway, in the earlier post we did see that research shows that dissolving milk teeth is signalled via increased IL-6 and we do know that increased IL-6, caused by allergies, can trigger worsening autism. 

So it does make sense, at least to me.

Regular uses of Sytrinol/Tangeretin looks a much safer bet than any NSAID.

If anyone tries it, particularly those who regularly use NSAIDs, let us all know.

PPARγ and Epilepsy

If you Google PPARγ and autism you will soon end up back at this blog.

For any sceptics, better to Google PPARγ and Epilepsy.  Epilepsy looks to be the natural progression of un-treated classic autism.  If this progression can be prevented, that should be big news.

Prevention is always better than a cure.  All kinds of conditions appear to be preventable, or at least you can minimize their incidence.  

Here are just the ones I have stumbled upon while researching autism:- Asthma  (Ketotifen), type 2 diabetes (Verapamil), prostate cancer (Lycopene) and many types of cancer (Sulforaphane).

There are of course types of epilepsy unconnected to autism, but epilepsy, seizures and electrical activity are highly comorbid with classic autism

PPARgamma, Epilepsy and Therapeutics

Abstract

Approximately 30% of people with epilepsy do not achieve adequate seizure control with current anti-seizure drugs (ASDs). This medically refractory population has severe seizure phenotypes and is at greatest risk of sudden unexpected death in epilepsy (SUDEP). Therefore, there is an urgent need for detailed studies identifying new therapeutic targets with potential disease-modifying outcomes. Studies indicate that the refractory epileptic brain is chronically inflamed with persistent mitochondrial dysfunction. Recent evidence supports the hypothesis that both factors can increase the excitability of epileptic networks and exacerbate seizure frequency and severity in a pathological cycle. Thus, effective disease-modifying interventions will most likely interrupt this loop. The nuclear transcription factor peroxisome proliferator activated receptor gamma (PPARy) regulates genes in anti-inflammatory, anti-oxidant and mitochondrial pathways. Preliminary experiments in chronically epileptic mice indicate impressive anti-seizure efficacy. We hypothesize that (i) activation of brain PPARy in epileptic animals will have disease modifying effects that provide long-term benefits, and (ii) determining PPARy mechanisms will reveal additional therapeutic targets. Using a mouse model of developmental epilepsy, we propose to (1) elucidate the cellular, synaptic and network mechanisms by which PPARy activation restores normal excitability;(2) demonstrate the significant contribution of mitochondrial health in pathologic synaptic activity in epileptic brain;(3) demonstrate inflammatory regulation of PPARy in epileptic brain;and (4) determine whether PPARy activation extends the lifespan of severely epileptic animals. The proposed studies, spanning in vivo and in vitro systems using a combination of techniques in molecular biology, electrophysiology, microscopy, bioenergetics and pharmacology, will provide insight into the interplay of seizures, mitochondria, inflammation and homeostatic mechanisms. The results will have tremendous, immediate translational potential because PPARy agonists are currently used for clinical treatment of Type II Diabetes. PPARy is under investigation as treatment for a wide variety of other neurological diseases with cell death and inflammation as common denominators;therefore, the results of this proposal will have a broad impact.

Public Health Relevance

Approximately 30% of people with epilepsy do not achieve adequate seizure control with current anti-seizure drugs (ASDs). This medically refractory population has severe seizure phenotypes and is at greatest risk of sudden unexpected death in epilepsy (SUDEP). Therefore, there is an urgent need for detailed studies identifying new therapeutic targets with potential disease- modifying outcomes.

Anticonvulsant potential of the peroxisome proliferator-activated receptor γ agonist pioglitazone in pentylenetetrazole-induced acute seizures and kindling in mice.

Activation of cerebral peroxisome proliferator-activated receptors gamma exerts neuroprotection by inhibiting oxidative stress following pilocarpine-induced status epilepticus.

Abstract

Status epilepticus (SE) can cause severe neuronal loss and oxidative damage. As peroxisome proliferator-activated receptor gamma (PPARgamma) agonists possess antioxidative activity, we hypothesize that rosiglitazone, a PPARgamma agonist, might protect the central nervous system (CNS) from oxidative damage in epileptic rats. Using a lithium-pilocarpine-induced SE model, we found that rosiglitazone significantly reduced hippocampal neuronal loss 1 week after SE, potently suppressed the production of reactive oxygen species (ROS) and lipid peroxidation. We also found that treatment with rosiglitazone enhanced antioxidative activity of superoxide dismutase (SOD) and glutathione hormone (GSH), together with decreased expression of heme oxygenase-1 (HO-1) in the hippocampus. The above effects of rosiglitazone can be blocked by co-treatment with PPARgamma antagonist T0070907. The current data suggest that rosiglitazone exerts a neuroprotective effect on oxidative stress-mediated neuronal damage followed by SE. Our data also support the idea that PPARgamma agonist might be a potential neuroprotective agent for epilepsy.

Possible involvement of PPAR-gamma receptor and nitric oxide pathway in theanticonvulsant effect of acute pioglitazone on pentylenetetrazole-induced seizuresin mice

CONCLUSION:

The present study demonstrates the anticonvulsant effect of acute pioglitazone on PTZ-induced seizures in mice. This effect was reversed by PPAR-γ antagonist, and both a specific- and a non-specific nitric oxide synthase inhibitors, and augmented by nitric oxide precursor, L-arginine. These results support that the anticonvulsant effect of pioglitazone is mediated through PPAR-γ receptor-mediated pathway and also, at least partly, through the nitric oxide pathway.

Note that elsewhere in this blog I have already highlighted that PPAR alpha agonists also seem to have an effect against epilepsy.  For example in this research:-

PPAR-alpha agonists as novel antiepileptic drugs: preclinical findings.

          

I was originally interested in PPAR-alpha, because of its role in regulating mast cells.  It seems that PPARγ also affects mast cells.

Activation of PPARγ  restores mast cell numbers and reactivity in all oxan-diabetic rats by reducing the systemic glucocorticoid levels

  

PPARγ modulators – drugs vs neutraceuticals vs functional food

It does seem that many people with inflammatory diseases, epilepsy, autism and even people who are obese, might greatly benefit from selective PPARγ agonists.

The choice would be between drugs, “nutraceuticals” and functional (good) food.

The drugs have not yet arrived that are safe and selective.  The current Thiazolidinedione (TZD) class of drugs TZDs tend to increase fat mass as well as improving insulin sensitivity and glucose tolerance in both lab animals and humans.

PPARγ as a metabolic regulator: insights from genomics and Pharmacology

Since its identification in the early 1990s, peroxisome-proliferator-activated receptor γ (PPARγ), a nuclear hormone receptor, has attracted tremendous scientific and clinical interest. The role of PPARγ in macronutrient metabolism has received particular attention, for three main reasons: first, it is the target of the thiazolidinediones (TZDs), a novel class of insulin sensitisers widely used to treat type 2 diabetes; second, it plays a central role in adipogenesis; and third, it appears to be primarily involved in regulating lipid metabolism with predominantly secondary effects on carbohydrate metabolism, a notion in keeping with the currently in vogue ‘lipocentric’ view of diabetes. This review summarises in vitro studies suggesting that PPARγ is a master regulator of adipogenesis, and then considers in vivo findings from use of PPARγ agonists, knockout studies in mice and analysis of human PPARγ mutations/polymorphisms.

As usual there are numerous “natural substances” that may also modulate PPAR-γ

Modulation of PPAR-γ by Nutraceutics as Complementary Treatment for Obesity-Related Disorders and Inflammatory Diseases

A direct correlation between adequate nutrition and health is a universally accepted truth. The Western lifestyle, with a high intake of simple sugars, saturated fat, and physical inactivity, promotes pathologic conditions. The main adverse consequences range from cardiovascular disease, type 2 diabetes, and metabolic syndrome to several cancers. Dietary components influence tissue homeostasis in multiple ways and many different functional foods have been associated with various health benefits when consumed. Natural products are an important and promising source for drug discovery. Many anti-inflammatory natural products activate peroxisome proliferator-activated receptors (PPAR); therefore, compounds that activate or modulate PPAR-gamma (PPAR-γ) may help to fight all of these pathological conditions. Consequently, the discovery and optimization of novel PPAR-γ agonists and modulators that would display reduced side effects is of great interest. In this paper, we present some of the main naturally derived products studied that exert an influence on metabolism through the activation or modulation of PPAR-γ, and we also present PPAR-γ-related diseases that can be complementarily treated with nutraceutics from functional foods.

Conclusion

If you are one of those people successfully using NSAIDs, like Ibuprofen, to reduce autistic behaviors, you might well be in the group that would benefit from Sytrinol/Tangeretin.

If NSAIDs never help resolve your autism flare-ups, Sytrinol/Tangeretin may not help either.

Tangeretin does appear to have other effects, beyond not needing to use Ibuprofen.  It was found to be a potent antagonist at P2Y2 receptors.

Suramin is another potent P2Y2 antagonist and Suramin is showing a lot of promise in Robert Naviaux’s autism studies at the University of California at San Diego.  Suramin is not viewed as safe for regular use in humans.