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Showing posts with label Naviaux. Show all posts
Showing posts with label Naviaux. Show all posts

Sunday 11 July 2021

Leaky ATP from either Mitochondria or Neurons in Fragile X and Autism

 


 

For leaky ATP, Popeye might want to try Dexpramipexole and

Suramin, or even the already approved Mirapex


If you are old enough to be a parent, you will have encountered problems with some kind of leak.  A leaky roof, a leaky pipe, a leaky washing machine, an air-conditioning unit... The list goes on, the older you get.

I have been preoccupied by fixing a leak recently.  We have a large roof terrace and, in the winter, water started leaking from the ceiling in the floor below.  I improvised a system to catch all the water, but still I had to find the source of the leak.

I did finally find the source of the problem and most importantly without digging up 95% of the terrace.  Now I have to put the 5% back together again.

Leaks are often extremely difficult to locate, because water always finds the easiest path and the dripping you see might have originated from a leak far away.  Nobody wants to fix leaks, because it can be a pretty thankless task and you can cause plenty of damage in the process, without solving the problem.  So, as with fixing autism, I ended up doing much of the fixing myself.  The damage had actually been there since the house was built, hidden under ceramic tiles.

I recently read about leaky ATP in Fragile-X, where ATP leaks from the mitochondria into the cell.

This fits neatly into Professor Naviaux’s belief that ATP is leaking from the cell into the extracellular space, as the basis for his concept of the cell danger response, as a unifying and treatable feature of most autism.

Sounds complicated?

Just think of it as bunch of leaks you need to fix.

 

 What is ATP? 

ATP has many functions:- 

·        It is the fuel your cells need to function.

·        It is a signalling molecule within a cell and importantly between different cells.

·        It is used to make your DNA

  

Mitochondria

Each cell in your brain contains many mitochondria and these are where ATP is produced. Mitochondria die and are replaced, whereas if the host brain cell dies, it is lost forever. Cell death in the brain is bad news.


The ATP – ADP Cycle 

You can think of ATP as a fully charged battery.  Once the energy has been used up the flat battery is called ADP and it goes back for recharging in the mitochondria.  It is a continuous cycle.

ADP is powered back to ATP through the process of releasing the chemical energy available in food; this is constantly performed via aerobic respiration in the mitochondria. This process is also called OXPHOS and has been covered in previous posts.  In most mitochondrial disease the problem is that one of the four mitochondrial enzyme complexes is insufficient; this means that the ATP-ADP cycle is restricted.  There is then insufficient energy to power the brain in times of peak energy requirement.  This can cause loss of myelination and ultimately cell death.

 



  

ATP in Fragile X

It looks like in Fragile X the mitochondria in the brain do not work properly. ATP is leaking from the mitochondria and this stops synapses from maturing. 

A synapse is just the junction between one neuron and its neighbour.

The immature synapse manifests as autistic behavior.  When you plug the leak with Dexpramipexole, a drug trialed for ALS and now asthma, dendritic spines mature and autistic behavior is reduced.

To what extent this leakage occurs in idiopathic autism is unknown, but we know that impaired dendritic spine formation/morphology is a key feature of most autism and that it can be modified, although the sooner you start the better the result will be.

It looks to me that some people diagnosed with mitochondrial disease based on blood tests may actually have leaking ATP which then affects metabolic pathways and shows up with odd blood test results, that is then misdiagnosed as mitochondrial disease.  Note that many people diagnosed with mitochondrial disease show no response to therapy.

In Professor Naviaux’s theory, the ATP leak is from the cell membrane, like the outer wall of the cell.  He thinks that ATP is leaking and this then sends a false danger signal to the rest of your brain.  This is his Cell Danger Response (CDR).  Because the brain thinks it is under attack it is set in a permanent pro-inflammatory state, this gets in the way of basic functions the developing brain needs to complete.  This might explain why the microglia (the brain’s immune cells) are found to be permanently activated in autism; this then means that they do not carry out their regular brain housekeeping activities very well, like pruning synapses.

Naviaux wants to plug the leaks in the cell wall using Suramin, which is an old anti-parasite drug made by Bayer, the giant German company.

The link between the Fragile X research from Yale and Naviaux’s work at UCSD is that ATP needs to be kept in the right place for the brain to function correctly.

Leaky ATP will cause you big problems.

 

 

Now for the supporting research

 

Leaky ATP in Fragile X

 

Fragile X syndrome traits may stem from leaky mitochondria

The persistent leak influences which metabolic pathway the cell uses to generate energy, the team discovered by using a technique called mass spectrometry. For example, fragile X neurons produce more enzymes associated with glycolysis — a pathway commonly used by immature cells — than do typical neurons. Previous studies have shown altered mitochondrial metabolism in people with other forms of autism2.

Adding dexpramipexole to the cells of fragile X mice decreased production of lactate dehydrogenase and other enzymes linked to glycolysis, suggesting that closing the leak causes the neurons to start to use different, more mature metabolic pathways.

Giving injections of dexpramipexole to fragile X model mice lessened their hyperactivity, repetitive behaviors and excessive grooming — traits that are reminiscent of those seen in people with autism and in those with fragile X syndrome. Mice that received the dexpramipexole injections also had neurons with more mature dendritic spines and decreased levels of protein synthesis.

Dexpramipexole has been tested in people with the neurological disease amyotrophic lateral sclerosis and found safe, but it is unclear how it would affect young people if taken over sustained periods of time.

 

ATP Synthase c-Subunit Leak Causes Aberrant Cellular Metabolism in Fragile X Syndrome

Loss of the gene (Fmr1) encoding Fragile X mental retardation protein (FMRP) causes increased mRNA translation and aberrant synaptic development. We find neurons of the Fmr1-/y mouse have a mitochondrial inner membrane leak contributing to a "leak metabolism." In human Fragile X syndrome (FXS) fibroblasts and in Fmr1-/y mouse neurons, closure of the ATP synthase leak channel by mild depletion of its c-subunit or pharmacological inhibition normalizes stimulus-induced and constitutive mRNA translation rate, decreases lactate and key glycolytic and tricarboxylic acid (TCA) cycle enzyme levels, and triggers synapse maturation. FMRP regulates leak closure in wild-type (WT), but not FX synapses, by stimulus-dependent ATP synthase β subunit translation; this increases the ratio of ATP synthase enzyme to its c-subunit, enhancing ATP production efficiency and synaptic growth. In contrast, in FXS, inability to close developmental c-subunit leak prevents stimulus-dependent synaptic maturation. Therefore, ATP synthase c-subunit leak closure encourages development and attenuates autistic behaviors.

 

Highlights 

·        ATP synthase c-subunit leak in Fragile X causes aberrant metabolism

·        Changes in ATP synthase component stoichiometry regulate protein synthesis rate

·        Inhibition of the leak normalizes synaptic spine morphology and Fragile X behavior

 

In Brief

Lack of FMRP in Fragile X neurons is associated with a leak in the ATP synthase, the blockade of which normalizes cellular and behavioral disease phenotypes.




 

Now they fix the leak using Dexpramipexole (Dex) and cyclosporine A (CsA)



 



 

We have found that the mitochondrial inner membrane leak of FX neurons and cells is caused by abnormal levels of ATP synthase c-subunit. The c-subunit leak causes persistence of a mitochondrial leak metabolic phenotype characterized by high glycolytic flux, high lactate levels, and increased levels of glycolytic and TCA enzymes. The leak also aberrantly elevates overall and specific protein synthesis; a decrease in c-subunit level or pharmacological inhibition of the ATP synthase leak reduces protein synthesis rates and decreases the levels of leak metabolism enzymes. In Fmr1/y synapses, stimulation-dependent protein synthesis is absent. This is correlated with a lack of stimulus induced EF2 phosphorylation and a lack of synthesis of the ATP synthase b-subunit. These abnormalities are readily reversed by ATP synthase leak inhibitors, suggesting that leak closure is required for the ATP-dependent phosphorylation of EF2 adjacent to mitochondria. EF2 phosphorylation may regulate the change in subsets of proteins synthesized and may be correlated with- the overabundant synthesis of enzymes supporting a high flux glycolytic/TCA cycle ‘‘leak’’ metabolism indicative of metabolic immaturity. Consistent with the hypothesis that the c-subunit leak is also a major cause of synapse immaturity, we find that inhibition of the ATP synthase leak allows the maturation of synapses and normalizes autistic behaviors.

 

 

 

Closing Leaky Mitochondria Halts Behavioral Problems in Fragile X, Study Suggests


“In Fragile X neurons, the synapses fail to mature during development. The synapses remain in an immature state and this seems to be related to their immature metabolism,” she said.

The investigators tested whether closing the leak to boost the efficiency of ATP production would lessen behavioral abnormalities.

They first saw that nerve cells treated with an ATP synthase inhibitor named dexpramipexole (Dex) — a form of the common Parkinson’s therapy Mirapex ER (pramipexole) and previously tested as a treatment for amyotrophic lateral sclerosis — increased the levels of ATP.

Two-day treatment with Dex also reversed autistic-like behaviors, namely excessive time spent grooming and compulsive shredding of the animals’ nests. The treatment also reduced hyperactivate behaviors.

“We find that inhibition of the ATP synthase leak allows for the maturation of synapses and normalizes autistic behaviors in a mouse model of [fragile X],” the team wrote.

Jonas and her team now intend to further test the effectiveness of this and other leak-closing therapies for improving learning.

The lab is conducting a study assessing the role of leaky membranes in memory formation. Findings could pave the way for novel therapeutics for fragile X and autism, as well as for Alzheimer’s disease.

 

 

 

Dr Naviaux and Suramin for Autism

 

I have covered Suramin in previous posts.  There is a presentation below by Prof Naviaux that is for lay people, it is good to hear directly from the man himself.

 

Autism Treatment, the cell danger response and the SAT1 trial

https://youtu.be/pqd_BoCeRUw




In essence he says that when cells are stressed, they leak ATP and this creates the cell danger response.  If you have suramin in your bloodstream, it plugs the ATP channels and stops it leaking out of the cell and so blocks the cell danger response.



It is the cell danger response that is causing the symptoms we see as autism.

  

Conclusion

Who to call to fix an ATP leak?

If it is a case of Fragile X, there looks to be potential solution, but you will definitely not find it at your local doctor’s office.

For a mouse with Fragile X, you might choose Dexpramipexole.  Dexpramipexole was developed as a therapy for ALS (motor neuron disease), but failed in phase 3 trials and is now being developed for asthma.

For a human, the logical place to start would be the already approved Mirapex, which is currently used to treat Parkinson's disease and restless legs syndrome.

Mirapex - a miracle for Fragile X?

Clearly somebody should make a clinical trial of the existing drug.

I expect what will happen is that the Yale researchers will come up will a new drug that can be patented as a novel therapy for Fragile X.  This way they get to make some money, but a decade is wasted.

Is leaky ATP from mitochondria an issue in broader autism, beyond Fragile X? That is still unknown, but the Yale researchers seem to think their work has potential application in both autism and Alzheimer’s.

In the case of broader autism, Dr Naviaux and his partner Kuzani have some competition from Paxmedica.  Both groups seek to monetize Dr Naviaux’s published research.

It looks like the German giant Bayer does not want to help either group.  Instead of just tapping into Bayer’s existing production of Suramin, Kuzani and Paxmedica will have to figure out how to produce Suramin.

This all helps us to understand why there still are no approved therapies for core Autism or indeed Fragile X and yet there is a mountain of research.  Too many barriers and interests to overcome.

If you want to fix leaky ATP any time soon, you will be doing it mainly by yourself.  This has been my experience with most other kinds of leak!

 




 

Saturday 5 December 2020

Suramin in China, where things can move fast – blocking Enterovirus-71 rather than treating Autism

The new Chinese and old Colonial, side by side in central Shanghai

  

I do not speak Chinese, but fortunately Google does.

I was sent some interesting links to some articles from China about Suramin, the potential autism therapy which many autism parents are eagerly awaiting.  Prepare for a long wait, but hopefully less long in China.

My original post on Suramin for autism can be found  in the link below:-


Suramin, the Purinome and Autism

 

 

I have never had a banner appear on my computer trying to sell me a Rolls Royce until today.  This is more proof, if I needed it, of how much China has changed since my first visit there as a teenager.  Back then there were a lot of bicycles; I still remember many were Flying Pigeon brand – not a name you forget. I just looked them up and since 1950, more than 500 million Flying Pigeon bicycles have been made - that is a lot bicycles.

I even went to see a factory still producing steam locomotives in Datong in the 1980s. They gave you a personal certificate of your visit, which I still have somewhere. 

Last year I was again in China and travelled on their ultra-modern high speed trains.  These run on purpose-built tracks, often running to totally new vast railway stations.  The network is massive with 36,000 km (22,000 miles) in total length and trains running at speeds up to 220 mph / 350 km/h.  The ride is perfectly smooth and the tickets are not so expensive.   The old train lines I used many years ago still exist and you can still take the “hard sleeper” to travel long distances overnight for little money, but not quite as cheap as it once was.  

 


 Things move fast in China, hopefully so will Suramin

Suramin is an approved drug, but it is almost impossible to get hold of, unless you are in a limited number of African countries affected by African Sleeping Sickness and River Blindness.  Suramin is made by the German giant Bayer and the brand name (below) is not very original.

 



I think the clever idea is the intranasal version now being developed in the US.

But why not just put this old drug from 1916 in a metered pump dispenser, in the same way the Alzheimer’s researchers put insulin in a nasal spray?  In autism, Vasopressin and Oxytocin are just popped into nasal sprays.  A few years in this blog I mentioned Dr Jay Goldstein who was treating people with TRH intranasally (he wrote a great book called Tuning the Brain – I actually bought it).

Tuning the brain eventually got Jay Goldstein into trouble. Though long “retired”, he has just published another book on ME/CFS.  Goldstein also used Ketamine eye drops and nasal spray.

I guess if he would have been among the first put this old Suramin drug in a nasal spray and see what happens. It quite possibly would help ME/CFS, as suggested by Dr Naviaux himself.

We saw in a post in 2014 that Professor Rita Levi-Montalcini had the clever idea of using home-made NGF eye drops to stave off decline in old age.  She was the first one to discover the existence of Nerve Growth factor (NGF). She became the first Nobel laureate to reach the age of 100.  The NGF eye drops did not do her any harm.

Your eyes are part of the Central Nervous System (CNS) and so an ideal entry point to target the brain. For nasal sprays the route to the CNS is via the trigeminal nerves and not much actually gets through (see below).  Due to the blood brain barrier many drugs taken orally cannot reach the brain.

 

Nose-to-Brain Delivery

The route of transfer of compounds through the nasal respiratory epithelium to the brain is via the trigeminal nerves 

A key advantage of the nose-to-brain route is the possibility of reducing plasma exposure, as has been demonstrated thus eliminating peripheral side effects.

 Simply dissolving the drug molecule in an aqueous phase has been used to administer molecules via the nose-to-brain route. The vast majority of clinical studies, which report pharmacological effects, have involved a solution of the drug in aqueous media delivered using a nasal delivery device

Oxytocin has also been delivered to the brain via the nasal route using a solution with a Cmax of 0.003% of a 10 μg dose being found in the brain. A solution of the human immunodeficiency virus replication inhibitor DB213 delivered the drug to the rat brain with a Cmax that was estimated at no more than 0.007% of the administered dose.

The addition of functional excipients to these solution formulations improves brain delivery via the nasal route. 

 

It may well be that Rita and Jay got it right by choosing eye drops over a nasal spray. Suramin eye drops? Not as crazy as it may sound.  Perhaps in China?

   

Back to China

 For several years there has been research looking at treating hand foot and mouth disease using Suramin.

Hand, foot, and mouth disease is common in children under five years old, but anyone can get it.

The illness is usually not serious, but it is very contagious. It spreads quickly at schools and day care centres.

 

Hand, foot, and mouth disease is caused by viruses that belong to the Enterovirus family.

Common causes of hand, foot, and mouth disease are:

  • Coxsackievirus A16 is typically the most common cause of hand, foot, and mouth disease in the United States. Other coxsackieviruses can also cause the illness.
  • Coxsackievirus A6 can also cause HFMD and the symptoms may be more severe.
  • Enterovirus 71 (EV-A71) has been associated with cases and outbreaks in East and Southeast Asia. Although very rare, EV-A71 has been associated with more severe diseases, such as encephalitis. 


Enterovirus 71 (EV-A71)


Suramin inhibits EV71 infection

Highlights

·        Suramin inhibits the proliferation of EV71 virus.

·        Suramin directly blocks the attachment of EV71 virion to host cell.

·        Suramin can be used as a potential clinical therapeutic against EV71 infection.

 

Abstract

Enterovirus-71 (EV71) is one of the major causative reagents for hand-foot-and-mouth disease. In particular, EV71 causes severe central nervous system infections and leads to numerous dead cases. Although several inactivated whole-virus vaccines have entered in clinical trials, no antiviral agent has been provided for clinical therapy. In the present work, we screened our compound library and identified that suramin, which has been clinically used to treat variable diseases, could inhibit EV71 proliferation with an IC50 value of 40 μM. We further revealed that suramin could block the attachment of EV71 to host cells to regulate the early stage of EV71 infection, as well as affected other steps of EV71 life cycle. Our results are helpful to understand the mechanism for EV71 life cycle and provide a potential for the usage of an approved drug, suramin, as the antiviral against EV71 infection.

 

 

The approved pediatric drug suramin identified as a clinical candidate for the treatment of EV71 infection - Suramin inhibits EV71 infection in vitro and in vivo

 Enterovirus 71 (EV71) causes severe central nervous system infections, leading to cardiopulmonary complications and death in young children. There is an urgent unmet medical need for new pharmaceutical agents to control EV71 infections. Using a multidisciplinary approach, we found that the approved pediatric antiparasitic drug suramin blocked EV71 infectivity by a novel mechanism of action that involves binding of the naphtalentrisulonic acid group of suramin to the viral capsid. Moreover, we demonstrate that when suramin is used in vivo at doses equivalent to or lower than the highest dose already used in humans, it significantly decreased mortality in mice challenged with a lethal dose of EV71 and peak viral load in adult rhesus monkeys. Thus, suramin inhibits EV71 infection by neutralizing virus particles prior to cell attachment. Consequently, these findings identify suramin as a clinical candidate for further development as a therapeutic or prophylactic treatment for severe EV71 infection.

 

 

Kangzhi Pharmaceutical has the rights to develop Suramin for hand foot and mouth disease in China and beyond. 

 

Kangzhi Pharmaceutical has developed a new indication for "Suramin Sodium" and is committed to the development of drugs for hand, foot and mouth disease 


Currently, there are no specific antiviral drugs for enteroviruses in the world, and support and symptomatic treatment are the main ones. Clinically, there is an urgent need to develop specialized drugs to treat patients with hand, foot and mouth disease who have been infected. Now that Kangzhi Pharmaceutical's suramin sodium for injection has been approved for clinical trials, it is undoubtedly a gospel for children with hand-foot-mouth disease and is expected to break the dilemma of treatment of hand-foot-mouth disease.

Kangzhi Pharmaceutical has been focusing on children's health for a long time. Under the guidance of "Children's Health Strategy" and "Excellent Strategy", the company insists on investing about 5% of its annual sales in research and development. In 2013, the company took the lead in establishing a post-doctoral scientific research station with children's drug research and development as the main direction in China, and was recognized as "Hainan Children's Drug Preparation Engineering Technology Research Center" in 2016. In order to solve the problem of no medicine for hand, foot and mouth disease, Kangzhi Pharmaceutical has invested heavily in the research and development of suramin sodium for injection.  

https://translate.googleusercontent.com/translate_c?depth=1&pto=aue&rurl=translate.google.com&sl=zh-CN&sp=nmt4&tl=en&u=https://finance.sina.com.cn/roll/2020-05-10/doc-iircuyvi2360398.shtml&usg=ALkJrhiXYaD6KShQuW26JhJlYDhdduUqyA

 For a long time, the anti-fever drug "Ruizhiqing (Nimesulide)" is Kangzhi Pharmaceutical's leading product in the children's medicine market. The company's revenue accounted for as high as 70% at one time. However, this product had previously suffered from side effects. Controversial, Kangzhi Pharmaceutical has no longer listed this product as a core competitive advantage in its financial report. Instead, it has given key exposure to another long-developed new drug for the treatment of hand, foot and mouth disease. ——Suramin Sodium for Injection.

It is understood that hand, foot and mouth disease is an infectious disease that is generally susceptible to infants and children under 5 years old. It continues to be prevalent at a fixed period every year. There is no specific medicine for targeted treatment. According to the statistics of the my country Center for Disease Control, the number of cases of hand, foot and mouth disease in China in 2018 was 2,533,310.

Obviously, if Kangzhi Pharmaceutical's new hand, foot and mouth disease drug can be successfully listed, it will become a major "cash cow" product of the company. By then, both performance and stock price will be effectively boosted. However, since this product was exposed by Kangzhi Pharmaceutical, the outside world only knows that this product will be "the world's first new medicine for the treatment of hand, foot and mouth disease", but its final market is still far away.

"The company has obtained the approval for the clinical trial of the drug, and the product has successfully completed the phase I clinical trial and will start the phase II clinical trial. If the clinical trial is successful and the marketing authorization is obtained, suramin sodium will become the world's first treatment for hand, foot and mouth. New medicine for disease.” In the 2019 financial report, Kangzhi Pharmaceutical introduced the latest development of suramin sodium.

As early as 2015, after Kangzhi Pharmaceuticals spent 18 million yuan to buy the patented technology of "Institutions and Methods for Treating Viral Diseases" of the Shanghai Pasteur Institute of the Chinese Academy of Sciences, and planned to invest 50 million yuan in suramin Subsequent research and development of sodium.

In 2018, after the application for the clinical trial of suramin sodium was submitted, it was quickly reviewed and approved according to the special review route. At that time, Hong Liping, vice chairman and vice president of Kangzhi Pharmaceuticals, said in an interview: "Suramin sodium for injection is approved for clinical trials, which is an important achievement of Kangzhi Pharmaceuticals in the development of new drugs. The company deeply feels the responsibility. With the help of the current national policy to encourage the spring breeze of clinically urgently needed therapeutic drugs, we will actively promote the development of clinical trials of the drug and promote the market of new drugs as soon as possible to help children with hand, foot and mouth disease get rid of the disease as soon as possible.

According to the company's secretary of the board of directors on the Shenzhen Stock Exchange, the clinical trial of suramin sodium is divided into 3 phases, and only phase 1 has been completed. The time of the clinical trial is uncertain.

It is reported that the new indication of suramin sodium for the treatment of hand, foot and mouth disease developed by Kangzhi Pharmaceutical has previously applied for an international invention patent through the PCT, and has successively obtained invention patent authorization in China, Japan, Singapore and the United States. The new Indonesian patent authorization will help to further leverage the advantages of independent intellectual property rights, promote the research of hand-foot-mouth disease treatment drugs, benefit the world's hand-foot-mouth disease patients, and enhance the core competitiveness of Kangzhi Pharmaceutical.

  

Conclusion 

It looks like there will eventually be at least 3 pharmaceutical companies selling Suramin.

  Bayer (Germany)

  Kangzhi Pharmaceutical (China)

  Paxmedica (USA), or really which ever Big Pharma they sell out to 

This is all good news for autism and hand foot and mouth disease. 

People do not like injections, nor side effects caused by your drug needlessly going everywhere in your body.

The nasal spray, or eye drops, look a good idea for autism and ME/CFS.

Hopefully the Chinese will move fast, like their trains, and bring their Suramin to the market.

 


In 2008 Arnold Schwarzenegger signed a bill to bring high speed rail to California.  The total system length would have been approximately 800 miles (1,300 km).  Where are we 12 years later?

The British are no better with their high-speed rail, but it is a very densely populated country. China's new rail lines were not built where the old lines ran. Spain actually has really good high-speed trains, that are not so expensive and a great way to get around the country.

Where are those autism drugs, "fast-tracked" for approval by the FDA? In the same place as Arnie’s model train set (going nowhere fast).

 

 




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.