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Showing posts with label Purinome. Show all posts
Showing posts with label Purinome. Show all posts

Friday, 26 May 2017

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)



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.
  


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.



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.







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:-


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. 




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.

















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.