Edging closer to targeting neuro-inflammation in autism via FPR2

 

 A thoughtful mouse in Naples

For many years, autism research has focused primarily on neurotransmitters such as GABA and glutamate. More recently, however, increasing attention has turned to another major contributor to brain function: the immune system.

Numerous studies have reported evidence of chronic microglial activation and elevated inflammatory cytokines in at least a subset of autistic people. The obvious question has always been:-

Can reducing neuro-inflammation improve the core features of autism?

A newly published study from researchers at the University of Naples suggests we may be edging closer to answering that question.

Rather than simply suppressing inflammation, they have taken a much more sophisticated approach by activating one of the body's own inflammation-resolution pathways. Their target is a receptor called Formyl Peptide Receptor 2 (FPR2), which has not been covered in previous posts.

 

Agonist MR-39 Supports Synaptic Health in the BTBR Mouse and Features a Favorable Safety Profile

Chronic unresolved inflammation is a common feature of several Central Nervous System (CNS) disorders, including autism spectrum disorder (ASD). We previously demonstrated that Formyl Peptide Receptor 2 (FPR2) activation by our agonist MR-39 reduced several inflammatory markers and improved social behavior in two validated animal models of ASD. Therefore, we decided to delve deeper into the potential of MR-39 as a drug for treating ASD. We first investigated the molecular mechanisms underlying the beneficial effects of MR-39 in BTBR mice. MR-39 significantly normalized pro-inflammatory cytokine release and NF-κB expression in the hippocampus and cortex, resulting in upregulation of synaptophysin protein levels, which, in turn, promote plasticity and correct abnormalities in dendritic spine morphology. Next, we characterized the safety and pharmacokinetic profile of MR-39 with respect to potential advancement for further pre- and clinical studies. We found that MR-39 was not genotoxic and safe to use since it had limited interaction with the majority of the targets associated with the adverse drug reaction. Consistently, a repeated-dose administration study evidenced no clinical signs attributable to treatment-related toxicity. On the other hand, MR-39 exhibited rapid hepatocyte clearance and interaction with efflux systems in vitro, suggesting possible limitations due to its pharmacokinetic properties. Finally, we explored multiple strategies to overcome MR-39’s low aqueous solubility, finding that the cosolvent approach can greatly enhance solubility and wettability. Overall, our study confirmed that promoting inflammation resolution with MR-39 can open new therapeutic options for ASD and that this compound has potential as a drug.

 

Why FPR2 is different

Most anti-inflammatory therapies work by blocking inflammatory pathways.

For example:

• statins reduce inflammatory signalling through multiple mechanisms
• pioglitazone shifts microglia towards a more reparative state via PPAR-γ
• ibudilast suppresses activated microglia
• low-dose naltrexone appears to reduce chronic glial activation through TLR4
• clemastine may reduce microglial activation while simultaneously promoting remyelination.

These are all potentially useful approaches, but fundamentally they are trying to dampen inflammation.

FPR2 works differently.

Inflammation is not simply switched on and then allowed to fade away. The body possesses an active programme that tells the immune system when the danger has passed and it is time to stop fighting and begin repairing damaged tissue.

FPR2 is one of the master regulators of this resolution of inflammation.

This distinction may prove extremely important in neurological disorders where persistent inflammation itself may be preventing normal synaptic development and plasticity.

 

Where is FPR2 found?

One reason FPR2 has attracted so much attention is that it is expressed in many of the cells involved in both inflammation and tissue repair.

Within the brain, FPR2 is found on:

• microglia - the brain's resident immune cells that monitor the environment, remove debris and regulate inflammation
• astrocytes - which support neurons, maintain the blood-brain barrier and participate in immune signalling
• neurons - suggesting FPR2 may influence synaptic plasticity and neuronal survival directly as well as indirectly through the immune system
• brain endothelial cells - which regulate communication between the bloodstream and the brain

Outside the brain it is expressed on many components of the innate immune system including neutrophils, macrophages, monocytes and several other immune cell types.

This broad distribution explains why FPR2 is now being investigated in such diverse conditions as Alzheimer's disease, stroke, multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, myocardial infarction and now autism.

Unlike many receptors that are confined to a single tissue, FPR2 appears to function as one of the body's master regulators of inflammation resolution. It helps coordinate the transition from an active immune response to tissue repair and restoration of normal homeostasis.

For autism this is particularly interesting because activating FPR2 could simultaneously calm activated microglia, reduce inflammatory cytokines, improve blood-brain barrier function and create an environment in which neurons and synapses can remodel more effectively.

Its widespread expression suggests that FPR2 is not simply controlling inflammation—it is coordinating the body's transition from defence to repair.

 

The experimental drug MR-39

The researchers tested a small molecule called MR-39, an activator of FPR2.

Interestingly, MR-39 was not originally developed as an autism therapy.

It emerged from research into neuro-inflammatory disorders, particularly Alzheimer's disease, illustrating an increasingly important trend in autism research: extending therapies developed for one neurological disorder into another when they target shared biological mechanisms.

Rather than developing drugs specifically "for autism", researchers are increasingly asking:

Which biological pathways are abnormal in autism, and are there drugs already being developed for those pathways?

This strategy has already given us therapies such as bumetanide, metformin, pioglitazone, statins and calcium-channel blockers.

MR-39 is another example.

An additional reason this approach is particularly attractive is that several studies have reported reduced circulating levels of Lipoxin A4 (LXA₄) in autistic children. LXA₄ is not just another anti-inflammatory molecule—it is one of the body's own specialised pro-resolving mediators (SPMs) and one of the principal activators of FPR2, already present in your body.

 

Decreased plasma levels of lipoxin A4 in children with autism spectrum disorders

The aim of this study was to evaluate the plasma levels of lipoxin A4 (LXA4), a mediator involved in the resolution of inflammation in Chinese children with autism spectrum disorders (ASD). From January 2013 to June 2014, a total of 150 children (75 confirmed ASD cases and 75 their age-matched and sex-matched control cases) participated in this study after consent was obtained from their parents. Clinical information was collected. Plasma levels of LXA4 were measured at baseline. The severity of ASD was assessed at admission using the Childhood Autism Rating Scale total score. The results indicated that the mean plasma levels of LXA4 were significantly lower in autistic children compared with the normal children (P<0.0001). There was a significant negative relationship between circulating LXA4 levels and severity of autism evaluated by Childhood Autism Rating Scale scores (P=0.006) after adjustment for the possible covariates.

These results suggested that autistic children had lower plasma LXA4 levels, suggesting an increased susceptibility to recurring inflammation in these samples.

 

In other words, the body already possesses a natural mechanism for activating this receptor and switching inflammation into its resolution phase.

If LXA₄ levels are indeed reduced in at least some autistic individuals, that natural "stop fighting, start repairing" signal may be weakened. MR-39 can therefore be viewed not as introducing an entirely artificial pathway, but as pharmacologically replacing or amplifying a biological signal that may already be deficient.

This provides a much stronger biological rationale for targeting FPR2 in autism than simply identifying it as another interesting receptor.

 

What did the new Italian study find?

Using the well-established BTBR mouse model of autism, the researchers found that after only eight days of treatment MR-39:

• significantly reduced the inflammatory cytokines IL-1β and TNF-α
• normalised NF-κB signalling
• increased levels of synaptophysin, an important marker of healthy synapses
• corrected abnormalities in dendritic spine morphology
• built upon previous work from the same laboratory showing improvements in social behaviour

One particularly encouraging finding was that MR-39 did not simply increase the number of synapses.

Instead, it appeared to improve their maturity.

The abnormal dendritic spines seen in the BTBR mice became much more like those found in healthy animals.

This is important because many forms of autism are characterised not simply by having too many or too few synapses, but by synapses that have failed to mature normally.

The findings therefore suggest that reducing chronic neuro-inflammation may allow existing neural connections to complete a more normal developmental programme, rather than simply creating new ones.

This may explain why MR-39 improved synaptic proteins and dendritic spine morphology without dramatically altering synapse number. Rather than forcing neurons to form new connections, the drug appears to create the biological conditions that allow normal developmental and repair processes to resume.

 

More than another mouse study

Many animal studies simply report behavioural improvements.

This paper goes considerably further.

The authors also examined:

• pharmacokinetics
• liver toxicity
• cardiac safety
• off-target effects
• genotoxicity
• metabolism
• formulation chemistry

In other words, they were already thinking like drug developers rather than purely academic scientists.

That makes this one of the more substantial preclinical autism studies published in recent years.

 

The challenges

MR-39 is not yet ready for human trials.

The authors identified several important limitations including poor oral bioavailability, rapid metabolism and potential cardiac and liver toxicity.

Fortunately, none of these appear insurmountable, and the compound was well tolerated in mice at therapeutic doses.

Like many first-generation research compounds, MR-39 itself may never become the final medicine.

Its greatest contribution may simply be demonstrating that FPR2 is a worthwhile therapeutic target.

 

Autism as a network disorder

One theme that has appeared repeatedly on this blog is that autism is probably best viewed not as a single biochemical defect, but as a network disorder.

Genes, mitochondria, immune activation, metabolism, ion channels, neurotransmitters and synaptic plasticity all interact to produce a stable pattern of brain function. Once established, that pattern may become a new homeostasis—a stable but abnormal equilibrium.

This helps explain why there is unlikely ever to be a single "autism drug".

A calcium-channel blocker may improve neuronal excitability.

A statin may reduce neuro-inflammation.

Pioglitazone may reprogramme microglia.

Clemastine may promote remyelination.

Bumetanide may restore inhibitory signalling.

Each addresses one part of the network.

The hope is not that one intervention completely resets the brain, but that multiple interventions gradually shift the network towards a healthier and more stable state.

Viewing autism as a network disorder naturally leads to a different therapeutic philosophy.

Instead of expecting one drug to correct every abnormality, the aim becomes rational polytherapy—combining carefully selected interventions that each influence a different component of the biological network.

One treatment might reduce neuro-inflammation.

Another might improve mitochondrial metabolism.

Another might restore inhibitory neurotransmission.

Another might promote remyelination.

Another might improve synaptic plasticity.

Individually these therapies may each produce only modest benefits.

Together, however, they may shift the entire network towards a healthier and more stable equilibrium.

This approach is already becoming familiar in other areas of medicine. Multiple sclerosis (MS) provides an excellent example. Twenty years ago, the primary goal of treatment was to suppress immune attack on myelin. Today, researchers increasingly recognise that long-term success also requires promoting remyelination, protecting neurons and encouraging the brain's own repair mechanisms. As a result, therapies such as clemastine, specialised pro-resolving mediators, neuroprotective agents and regenerative approaches are being investigated alongside traditional immunomodulatory drugs.

The philosophy is changing from simply stopping damage to actively promoting recovery.

I believe autism research is beginning to move in the same direction.

FPR2 is particularly interesting because it sits relatively high in the hierarchy of inflammatory regulation. Rather than blocking one inflammatory pathway, it appears to activate one of the brain's own programmes for restoring homeostasis. As such, future FPR2 activators/agonists may eventually become one component of a broader polytherapy approach that aims not merely to suppress symptoms, but to help the brain repair and reorganise itself.

  

Linking FPR2 with the Cell Danger Response

One striking aspect of this work is how well it fits with Robert Naviaux's Cell Danger Response (CDR) hypothesis.

Naviaux proposes that when cells encounter infection, toxins, trauma or metabolic stress they switch into a protective emergency programme.

Mitochondria alter their metabolism.

ATP is released outside cells as a danger signal.

Inflammatory pathways become activated.

Normal cellular communication becomes secondary to survival.

This response is entirely normal.

The problem arises if cells fail to exit this emergency state after the original danger has passed.

Viewed in this way, FPR2 could represent one of the mechanisms that helps cells transition out of the Cell Danger Response and back towards normal homeostasis.

Although this link remains speculative, it provides an intriguing framework that connects mitochondrial signalling, neuroinflammation and synaptic repair.

Interestingly, the two fields approach the problem from opposite directions.

Naviaux focuses on danger signalling—how cells detect injury and enter an emergency programme.

The FPR2 researchers focus on resolution signalling—how the immune system recognises that the danger has passed and initiates tissue repair.

These may simply represent different stages of the same biological programme.

One explains how the emergency begins.

The other may explain how it ends.

Ultimately, both point towards the same biological transition:

 

Stop defending. Start repairing.

Rather than directly repairing neurons, FPR2 activation may simply remove one of the major barriers preventing the brain from repairing itself.

 

Helping the body repair itself

Perhaps the most interesting lesson from this paper extends well beyond autism.

For decades drug development has largely focused on blocking abnormal pathways.

Block an enzyme

Block a receptor

Block a cytokine

Increasingly, medicine appears to be moving towards a different philosophy.

Many of the body's repair mechanisms already exist.

Stem cells migrate to damaged tissue.

Microglia clear cellular debris.

Specialised lipid mediators resolve inflammation.

Neurons remodel synaptic connections.

Oligodendrocytes repair myelin.

The challenge is often not that these systems are absent, but that they have become stalled or trapped in an abnormal steady state.

FPR2 appears to be one of the molecular switches that tells the immune system:

"The danger has passed. Stop fighting. Start rebuilding."

That may explain why FPR2 is attracting attention not only in autism, but also in Alzheimer's disease, stroke, multiple sclerosis and cardiovascular disease.

Rather than overriding biology, it appears to encourage biology to resume doing what evolution designed it to do.

 

Can we simply increase Lipoxin A4 instead?

An obvious question is: if autistic children have reduced levels of Lipoxin, why not simply treat with Lipoxin? Unfortunately, this is not practical. Like many of the body's own signalling molecules, Lipoxin is chemically unstable and has a biological half-life measured in minutes. It is rapidly broken down after being produced, making it a poor drug candidate.

This is the main reason researchers focus on developing stable FPR2 activators like MR-39, which are engineered to mimic the beneficial effects of Lipoxin while remaining active in the body for much longer. 

Another strategy is to encourage the body to produce more of its own Lipoxin. Unlike the resolvins, which are derived from omega-3 fatty acids, Lipoxin is synthesised from arachidonic acid (AA)—an omega-6 fatty acid that is already abundant in most people's cell membranes. The limiting factor here is not the availability of raw materials, but the activity of the specific enzymes required to convert that arachidonic acid into Lipoxin. At present, no supplement has been convincingly shown to raise Lipoxin levels in humans. 

However, there is growing evidence that regular aerobic exercise promotes the production of the body's broader family of specialised pro-resolving mediators (SPMs). For now, until stable analogues or molecular activators clear clinical trials, optimizing these natural physiological pathways remains our best practical tool.

 

Conclusion

MR-39 itself may never become an approved medicine. What encourages me far more is the direction in which neuroscience is moving. Research is gradually shifting away from searching for a single defective molecule and towards understanding the brain as a dynamic biological network capable of adaptation, repair and recovery.

The same trend is appearing across medicine. Many of today's most exciting therapies no longer attempt to repair the body themselves. Instead, they help the body repair itself. Whether through inflammation-resolution pathways such as FPR2, remyelination with clemastine, metabolic reprogramming with pioglitazone, restoration of inhibitory signalling with bumetanide, or perhaps one day therapies based on the Cell Danger Response, the underlying philosophy is becoming remarkably similar. The objective is not simply to suppress disease. It is to restore the conditions under which the brain can heal itself.

Increasingly, researchers are discovering that many chronic diseases are characterized not simply by excessive inflammation, but by a failure of that inflammation to resolve properly. Rather than continually developing stronger anti-inflammatory drugs to stomp out symptoms, the future lies in identifying the biological signals that tell the brain it is finally safe to stop defending itself and start developing normally again. If that philosophy proves correct, future autism treatment may consist of carefully selected combinations of therapies, each nudging a different part of the network in the same direction. Individually they may produce modest improvements, but together they may help the brain escape an abnormal equilibrium and settle into a healthier one.

In my specific case, I think we have already achieved this with my son’s Polypill therapy.

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!

 

 

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 C_max 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 C_max 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).