UA-45667900-1
Showing posts with label ShK peptides. Show all posts
Showing posts with label ShK peptides. Show all posts

Wednesday 31 October 2018

TSO for Autism with Allergies? Published after 5 years - Also Ponstan again


As we know, things often do not move fast in the world of medical research, at least when it comes to autism.
Back in 2014 I wrote some posts about a novel immuno-modulatory therapy, based on TSO, a harmless gut parasite, developed for autism by one parent. He then shared it with Eric Hollander at The Albert Einstein College of Medicine. Then a small biotech company called Coronado, tried to develop TSO to treat a variety of inflammatory conditions, including autism.

A pilot trial in autism was funded by the Simons Foundation and Coronado.
Coronado did not achieve the desired results in their ulcerative colitis TSO trials, so their share price took a dive and they later changed their name to Fortress Biotech. It looks like they have given up on TSO.
The autism Dad, Stewart Johnson, who originally came up with the idea has not updated his TSO website since 2011.


I do wonder if he continues to give TSO to his son. The good thing is that he fully documented his son's treatment, shared it with a leading autism researcher and has left the information in the public domain.    
The research data from the pilot trial has finally been published.


OBJECTIVES:

Inflammatory mechanisms are implicated in the etiology of Autism Spectrum Disorder (ASD), and use of the immunomodulator Trichuris Suis Ova (TSO) is a novel treatment approach. This pilot study determined the effect sizes for TSO vs. placebo on repetitive behaviors, irritability and global functioning in adults with ASD.

METHODS:

A 28-week double-blind, randomized two-period crossover study of TSO vs. placebo in 10 ASD adults, ages 17 to 35, was completed, with a 4-week washout between each 12-week period at Montefiore Medical Center, Albert Einstein College of Medicine. Subjects with ASD, history of seasonal, medication or food allergies, Y-BOCS ≥ 6 and IQ ≥70 received 2500 TSO ova or matching placebo every two weeks of each 12-week period.

RESULTS:

Large effect sizes for improvement in repetitive behaviors (d = 1.0), restricted interests (d = 0.82), rigidity (d = 0.79), and irritability (d = 0.78) were observed after 12 weeks of treatment. No changes were observed in the social-communication domain. Differences between treatment groups did not reach statistical significance. TSO had only minimal, non-serious side effects.

CONCLUSIONS: 

This proof-of-concept study demonstrates the feasibility of TSO for the treatment of ASD, including a favorable safety profile, and moderate to large effect sizes for reducing repetitive behaviors and irritability.


some excerpts:-

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by marked deficits in two core symptom domains: social-communication, and repetitive behaviors and restricted interests. Current literature supports a link between neuroinflammation, imbalanced immune responses, and ASD. Characteristic cytokine profiles of Th2 anti-inflammatory and Th1 proinflammatory cytokine responses have been reported in ASD. Additionally, some individuals with ASD demonstrate an amelioration of symptoms during fever episodes. This suggests a role for immune-inflammatory factors, as fever is a cardinal symptom of infectious and inflammatory processes, and induces the secretion of pro-inflammatory cytokines which are part of an autoregulatory loop. Early in neurodevelopment, microglia play a protective role in promoting neurogenesis, suppressing inflammation and eliminating inhibitory synapses. Pro-inflammatory cytokines are known to activate microglia, which in turn secretes cytokines that participate in the inflammation process. There is evidence for neuroglial activation and neuroinflammation in the cerebral cortex, cerebellum and white matter of individuals with ASD, which relates to an increase of glial-derived cytokines. Additionally, viral infection during pregnancy correlates with increased frequency of ASD in offspring. This is modeled in rodents subjected to maternal immune activation (MIA), which results in autism-like behavioral abnormalities in their offspring.

Both T helper 17 (TH17) cells and the effector cytokine interleukin-17a (IL-17a), are present in mothers who have MIA-induced behavioral abnormalities in their offspring. In this animal model of MIA, the abnormal autistic-like behavior in offspring is prevented by maternal treatment with an anti-inflammatory cytokine IL-6 antibody. Additionally, recent studies suggest that therapeutic targeting of TH17 cells in susceptible pregnant mothers may reduce the likelihood of bearing children with inflammation-induced ASD-like phenotypes. In sum, due to the inflammatory mechanisms implicated in the development and symptomatology of ASD, immunomodulatory interventions should be explored as an experimental therapeutics’ pathway.

The study of helminth worms, such as Trichuris Suis Ova (TSO), for the treatment of autoimmune disorders emerged from the “hygiene hypothesis”. This hypothesis states that stimulation of the immune system by infectious agents, such as microbes that stimulate normal immune responses, is protective against the development of inflammatory diseases, and that due to a rise in hygiene in urban settings there are less protective microbes in humans. This subsequently leads to an increase in autoimmune inflammatory disorders, including multiple sclerosis, inflammatory bowel disease, asthma, allergic rhinitis and possibly ASD. The interaction of the developing immune system with microorganisms, including helminths, may be an important component of normal immune system maturation. TSO has been studied in clinical trials of other immune-inflammatory disorders such as allergies, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, and multiple sclerosis with mixed results. This is the first such study in ASD or any neurodevelopmental disorder.  

The porcine whipworm TSO is proposed to work through multiple mechanisms, including interference with antigen presentation, cell proliferation and activation, antibody production, and modulation of dendritic cells. In addition to the induction of regulatory cells, TSO may modify the cytokine profiles released by the local inflammatory cells. Helminths, including TSO, are well known to induce tolerance in their hosts via differential modulation of increased anti-inflammatory Th2 cytokine (IL-4, IL-5, IL-10, IL-13) and decreased pro-inflammatory Th1 and Th17 cytokine (IL-1, IL-12, IFN-γ, TNF-α, IL-6) responses. Th2 cell induction leads to strong IgE, mast cell and eosinophil response, while cytokines IL-4 and IL-13 trigger intestinal mucous secretion, enhance smooth muscle contractibility, and stimulate fluid secretion in the intestinal lumen. Additional studies have shown that a similar exposure to TSO results in the augmentation of the anti-inflammatory Th2 response, a dampening of the toll-like receptor (TLR)-induced proinflammatory Th1 and Th17 responses, and an increased presence of myeloid and plasmacytoid dendritic cells, which are antigen producing cells that stimulate T-cells.

Our subjects were part of an ASD subgroup, and were high functioning adults, as defined by an IQ greater than 70, with a history of seasonal, medication, or food allergies, and/or a family history of autoimmune illness. Thus, results may not be generalizable to a larger more heterogeneous ASD population.

This study suggests that immune-modulating agents could be a useful therapeutic approach to address certain domains in individuals with ASD. Those that will benefit the most are likely to have marked restricted and repetitive behaviors and irritability. Future studies are needed to replicate these preliminary findings in larger samples, and effect sizes support future trials with 25 subjects per group in a parallel design study. Alternatively, they could be completed in a younger population, stratified for higher baseline severity, and using other immunomodulatory agents.  

Conclusions 

This trial provided key data necessary for planning further definitive studies of TSO in the ASD population. TSO was observed to improve symptoms in the restricted and repetitive patterns of behavior domain of ASD. These symptoms map onto the positive valence systems and cognitive systems of the NIMH Research Domain Criteria (RDoc) matrix, which provides an integrative research framework for the study of mental disorders. Specifically, the Approach Motivation, Habit and Cognitive Control constructs of the matrix are targeted by TSO. Future trials should continue to integrate the RDoc framework, and be conducted in more homogeneous syndromal forms of ASD with marked immune and microglial abnormalities. 

Acknowledgements:

This work was supported by the Simons Foundation under Grant number 206808, and by Coronado Biosciences. Coronado Biosciences also provided both TSO and the matching placebo. This data was presented at the International Meeting for Autism Research (2015, Poster 20516), and the American College of Neuropsychopharmacology Conference (2013, Panel and Poster T177).  


My posts related to parasites and autism are below. The role of the ion channel Kv1.3 is interesting.


                            

Personalized Medicine
The problem with personalized medicine, like Stewart Johnson and the TSO treatment for his son, is that it may be just too personalized to apply to most other people.  As a result, investing money in the many possible autism treatments is a highly risky business. Many potential autism treatments like, Arbaclofen, are stumbled upon by accident or in a n=1 trial. 
Our reader Knut Wittkowski has got backing for his mefenamic acid-based therapy to halt the progress of autism to severe and non-verbal.
He made a deal with Q BioMed and the drug is now called QBM-001.  The idea was to modify the already existing painkiller Ponstan (which is OTC in many countries) so that it had reduced side effects and most importantly can be patented.


The treatment window during which the child is sensitive to the effects of the drug is proposed to be 12-24 months.
Q BioMed want to submit an orphan drug application in 2019. The problem with that is that autism is now very common and it is hard to see how an autism drug for children up to 2 years of age would qualify. You cannot really tell at 12 months if someone is going to have mild or severe autism, so you would have to give it to everyone with a diagnosis.
Orphan drugs are for rare conditions and have stronger/longer patent protection to allow drug developers to get their money back. 
Nonetheless, good luck to Knut. 
The original post on Ponstan and Knut’s work.


Ponstan is widely available outside of the US. It is particularly good at lowering temperature in children during fevers.

Sensitive periods and treatment windows are the topics of a forthcoming post. We did earlier look at critical periods, which are key times during the development of the brain.  It is important to know when these are, because you need to have your therapy in place at these times. Sensitive periods are the time periods when a therapy can be effective. Correcting some defects is only possible within these critical windows and this needs to be understood by those planning clinical trials.

Knut is a rare researcher who has fully grasped this.









Monday 23 February 2015

Nystatin in autism - a potent Potassium Channel Kv1.3 blocker (anti-inflammatory) or an antifungal/candida treatment?


Today’s post will go against some people’s understanding of autism and inflammatory bowel disease.

Just as there is a belief that heavy metals are a problem in autism there is another is another belief that candida is involved in autism and indeed inflammatory bowel disease (IBD).  Various types of IBD are highly comorbid with autism, but most people with IBD do not have autism.
The most common treatment for candida is an antifungal medicine called nystatin.  This drug is a cheap and widely available.

But nystatin has another property, it is a highly effective blocker of the potassium channel Kv1.3.

Regular readers will recall that this ion channel is key mediator in the inflammatory process, it is a target in many inflammatory conditions such as IBD and indeed autism.  Those little helminths (TSO) parasites that are being researched for both autism and IBD were found to reduce inflammation by releasing their own Kv1.3 blocker which stops the host (human or animal) from rejecting them.






Abstract: Background: Autism children were reported to have gastrointestinal problems that are more frequent and more severe than in children from the general population. Although many studies demonstrate that GI symptoms are common in autism, the exact percentage suffering from gastrointestinal (GI) problems is not well known, but there is a general consensus that GI problems are common in autism. The observation that antifungal medications improve the behavior of autism children, encourage us to investigate their intestinal colonization with yeasts. Aim of the work: The purpose of this work was to investigate the intestinal colonization with yeasts in autistic patients and to assess the role of yeast as a risk factor to cause autism behavior. Patients and methods: The study included 83 cases diagnosed as autistic children referred from the neuro-pediatric clinic and 25 normal children as a control group. All children under the study came to Phoniatric clinic, during the period from 2010 to 2012, complaining of delayed language development with autistic features. Children in this study were classified into 2 groups; control and study groups. All children were subjected to interview, E.N.T examination, language assessment, Childhood Autistic Rating Score (CARS), stool culture for Candida albicans, complete audiological and psychometric evaluation. Results: There was significant relation between the autistic children and heavy growth of Candida albicans in stool culture. Conclusion: The high rate of Candida albicans intestinal infection in autistic children may be a part of syndrome related to immune system disorders in these patients.





Conclusion: Candida albicans infection may be a part of syndrome related to the immune system and depends on genetic basis of autism, or Candida albicans may be etiological factor lead to excessive ammonia in gut which is responsible of autistic behavior in children. More researches are needed to clarify the exact mechanism by which Candida albicans affects autistic children.


  
In another study the results were not so clear:-



This study was done by James Adams (of the Autism Research Institute, former home of DAN).  According to Wikipedia, Adams' research has been described as "a laundry list of autism woo"; I think he is well intentioned.

You would have expected him to find Candida, but he did not. 

Note that they did not find any parasites either, although they did give up testing after the first 20 results were negative (not very scientific, I think).  Regular readers will know that some “holistic doctors” insist that parasites are the cause of autism.
  

Yeast

The presence of yeast was determined by both culture and by microscopic observation. Yeast was only rarely observed by culture in the autism or typical groups, and the difference between the two groups was not significant, as shown in Table Table5.5. Yeast was more commonly observed microscopically, but again the difference between the two groups was not significant.

Parasitology

The parasitology test was used on the first 20 autism samples only, which were all negative. It was then decided to do no additional testing on other samples

  
The finding that yeast levels were similar in both the autistic and control group is interesting, as there has been a great deal of speculation that yeast infections are a major problem in autism. Our data indicates that yeast is present at normal levels in the stool of this group of children with autism. A study by Horvath and Perman [21] reported that 43% of children with autism undergoing endoscopies had a positive fungal culture for yeast in their duodenal juice, vs. 23% of age-matched controls with other gastrointestinal problems requiring endoscopies. Since their study involved children with severe enough symptoms to warrant endoscopies, the greater symptom severity may explain some of the difference with our study. Since the survey by the Autism Research Institute of over 25,000 parents' reports that parents find antifungals to be one of the most effective medications for improving behavior [44], our findings are puzzling. It is possible that children with autism are more sensitive to even a normal level of yeast. Also, it is possible that antifungals have other effects, such as reducing inflammation.

  
Which Study to believe?

I have to say that I give more credence to the first study, which is from Egypt.

I think that autism in Egypt is likely to be the “real deal”.  People with severe autism will likely have associated auto-immune/inflammatory conditions and this will include abnormal GI conditions.

Also, the more severe the autism, the more restrictive the diet is likely to be, which will affect what grows inside the intestines.   

   
Ion Channels and Channelopathies

Ion channels are complex, but fortunately there are not that many of them, unlike genes.

A good source of information is provided by École polytechnique fédérale de Lausanne, on the banks of lake Geneva.  On their Channelpedia site you can see a nice entry on the potassium channel Kv1.3.  It may all look rather too complicated, but there under the Scorpion toxin, is a very common drug, Nystatin.



Interactions


PAP-1

MbCD and MbCD/C

Zn

Leukocyte Subunits effect Kv1.3

Cluster at C-terminus

Kv1.3 associates with Kv1.5

Kv1.3 forms heteromeric channels

Scorpion toxin ADWX-1 is a pore blocker of Kv1.3 channel without affecting its kinetics

Nystatin

The concentrations for nystatin and its structural analog, amphotericin B, required to produce half maximal inhibition (IC50) of the current were estimated to be about 3 and 60 microM, respectively. The effects of nystatin on the amplitude and inactivation of Kv1.3 currents were not voltage-dependent. In inside-out patches, tetraethylammonium (TEA) produced a rapid block of Kv1.3 currents upon the onset of a voltage pulse, while the inhibition by nystatin developed slowly. When co-applied with TEA, nystatin potentiated the extent of the TEA-dependent block, and the kinetic effect of nystatin was slowed by TEA. In summary, nystatin, a compound frequently used in perforated patch recordings to preserve intracellular dialyzable components, specifically inhibited the potassium channel Kv1.3 at concentrations well below those required for perforation



KCa3.1 is related to acute immune responses and Kv1.3 is related to chronic immune responses, the combined administration with Kv1.3 and KCa3.1 inhibitors is likely to enhance their effects in autoimmune disorders or graft rejection

We know that Kv1.3 is widely expressed in the brain, but is it expressed in the intestines of people with inflammatory/auto-immune conditions?

We do not have far to look and since we know that ulcerative colitis is comorbid with autism, we can stick with that


Abstract

BACKGROUND AND AIMS:

Potassium channels, KV1.3 and KCa3.1, have been suggested to control T-cell activation, proliferation, and cytokine production and may thus constitute targets for anti-inflammatory therapy. Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by excessive T-cell infiltration and cytokine production. It is unknown if KV1.3 and KCa3.1 in the inflamed mucosa are markers of active UC. We hypothesized that KV1.3 and KCa3.1 correlate with disease activity and cytokine production in patients with UC.

METHODS:

Mucosal biopsies were collected from patients with active UC (n=33) and controls (n=15). Protein and mRNA expression of KV1.3 and KCa3.1, immune cell markers, and pro-inflammatory cytokines were determined by quantitative-real-time-polymerase-chain-reaction (qPCR) and immunofluorescence, and correlated with clinical parameters of inflammation. In-vitro cytokine production was measured in human CD3(+) T-cells after pharmacological blockade of KV1.3 and KCa3.1.

RESULTS:

Active UC KV1.3 mRNA expression was increased 5-fold compared to controls. Immunofluorescence analyses revealed that KV1.3 protein was present in inflamed mucosa in 57% of CD4(+) and 23% of CD8(+) T-cells. KV1.3 was virtually absent on infiltrating macrophages. KV1.3 mRNA expression correlated significantly with mRNA expression of pro-inflammatory cytokines TNF-α (R(2)=0.61) and IL-17A (R(2)=0.51), the mayo endoscopic subscore (R(2)=0.13), and histological inflammation (R(2)=0.23). In-vitro blockade of T-cell KV1.3 and KCa3.1 decreased production of IFN-γ, TNF-α, and IL-17A.

CONCLUSIONS:

High levels of KV1.3 in CD4 and CD8 positive T-cells infiltrates are associated with production of pro-inflammatory IL-17A and TNF-α in active UC. KV1.3 may serve as a marker of disease activity and pharmacological blockade might constitute a novel immunosuppressive strategy.


So now we have some evidence that Kv1.3 is involved in the inflammatory response within the intestines of people with inflammatory bowel disease (IBD).

Now we just need to look at what happens when you give Nystatin to people with IBD.

Since we do have to link all this back to Candida, let us look for people with IBD claiming that the problem was all about Candida.

If you google Crohns disease (a type of ulcerative colitis/IBD) you will find numerous reference to the benefit of Nystatin and again the assumption that “yeast overgrowth” is somehow the cause of the disease.  Lots of "holistic" doctors etc.


Why do so many people with autism benefit from Nystatin?

We have seen why some people with GI inflammation should find Nystatin very helpful, it will act locally as an immuno-suppressant.  

By reducing this inflammation there will be a reduction in inflammatory cytokines like IL-6.  But the whole idea of Nystatin being safe for children with autism is that it does not enter the blood stream, in stays inside the intestines.


Leaky Gut

Many people subscribe to the notion of the “leaky gut” in autism.  If indeed the gut was leaky, the Nystatin might leak out.  It would then act as a Kv1.3 blocker elsewhere in the body.  It may, or may not, be able to cross the blood brain barrier.

There is now some scientific evidence to show that  “leaky gut” is a real phenomenon.

In people with ulcerative colitis, of course the gut is leaking.  Blood is coming in and therefore other things can flow the other way.

In healthy people, Nystatin will stay almost entirely where it should, within the intestines.  In people with “leaks” it would seem likely that some will leak out.  In these people we might expect a greater effect.

We do know that inflammatory activity within the gut can transmitted elsewhere in the body via the vagus nerve.  This means that reducing inflammation within the GI will reduce the pro-inflammatory signalling sent around the body via the vagus nerve, even with no "leaky gut".  

This may indeed sound very odd, but very promising results are now being found in treating people with arthritis (an inflammatory condition, where IL-6 plays a key role) using implanted electrical devices that affect the vagus nerve.  Vagus nerve stimulation is not pseudoscience, even though it does sound like it should be.

  
My conclusion

The “father” of ARI and the DAN movement, Dr Bernard Rimland, a research psychologist, suggested that a small proportion of people diagnosed with autism had nothing more than an overgrowth of candida, caused by the frequent use of antibiotics.

It does seem that very many things can lead to “autism” and this diagnosis is now equally applied to people with very mild symptoms and those with debilitating ones.  I imagine that Bernie may indeed have been right; in a small number of people the problem may indeed be yeast.  However, given the relatively large number of people with autism (and IBD) who find Nystatin very helpful, I think the real issue is inflammation and  KV1.3.  The people who respond to Nystatin would very likely also respond to those TSO helminths, and even Stichodactyla toxin (see later).

One problem with regular use of antifungal medication is that you are going to kill off not just the candida.  A healthy gut is supposed have all sorts of things living in it.   

For me, the conclusion is to go back to the ion channels and look not just for KV1.3 blockers but also KCa3.1.  There are plenty of people doing just this, but not for autism, for example:-




Kv1.3 blockers do exist and they include:-

·        Curcumin (problem is low bioavailability)

·        Acacetin (rarely studied and mainly used by bodybuilders)

Abstract

Under normal conditions in the brain, microglia play roles in homeostasis regulation and defense against injury. However, over-activated microglia secrete proinflammatory and cytotoxic factors that can induce progressive brain disorders, including Alzheimer's disease, Parkinson's disease and ischemia. Therefore, regulation of microglial activation contributes to the suppression of neuronal diseases via neuroinflammatory regulation. In this study, we investigated the effects of acacetin (5,7-dihydroxy-4'-methoxyflavone), which is derived from Robinia pseudoacacia, on neuroinflammation in lipopolysaccharide (LPS)-stimulated BV-2 cells and in animal models of neuroinflammation and ischemia. Acacetin significantly inhibited the release of nitric oxide (NO) and prostaglandin E(2) and the expression of inducible NO synthase and cyclooxygenase-2 in LPS-stimulated BV-2 cells. The compound also reduced proinflammatory cytokines, tumor necrosis factor-α and interleukin-1β, and inhibited the activation of nuclear factor-κB and p38 mitogen-activated protein kinase. In an LPS-induced neuroinflammation mouse model, acacetin significantly suppressed microglial activation. Moreover, acacetin reduced neuronal cell death in an animal model of ischemia. These results suggest that acacetin may act as a potential therapeutic agent for brain diseases involving neuroinflammation.

·        Progesterone (as a hormone, has many other effects)

·        Verapamil (already in the PolyPill)



The most unusual/interesting comes from Cuba:-

Stichodactyla toxin





In humans, a polymorphism in the Kv1.3 promoter is associated with impaired glucose tolerance and with lower insulin sensitivity (11). These results suggest that selective Kv1.3 blockers might have use in the management of obesity and insulin resistance


Because pancreatic beta cells, which have Kv3.2 channels, are thought to play a role in glucose-dependent firing, ShK, as a Kv3.2 blocker, might be useful in the treatment of type-2 diabetes.
  
You may recall we already saw in this blog the older people taking Verapamil (for heart problems) did not develop type 2 diabetes. According to the table below, ShK toxin is a Kv3.2 blocker in humans, but Verapamil only works in rats.








Since it looks like selective Kv1.3 blockers may prevent/treat obesity, you can expect them to be attractive targets for pharmaceutical companies.  This is a disease of the 21st century.

The spin-off might later be a cost-effective treatment for inflammatory conditions like IBD and autism.

The clever new arthritis treatments, that could be used in autism, are hugely expensive.






Tuesday 12 August 2014

Immunomodulatory Therapy in Autism - Potassium Channel Kv1.3, Parasitic Worms, and their ShK–related peptides



Regular readers of this post will know that I believe that Immunomodulatory therapy has great promise for treating various subtypes of autism.  In effect, I want to bring the over-activated immune system back under control.  Two methods that appeal are:-

·        The steroid, Prednisone, because it is cheap and though it has side effects, they are very well understood. It also has been shown to be effective in autism and related conditions like PANDAS and Landau-Kleffner syndrome (LKS)

·        Parasitic worms appeal because they are known to have beneficial effect in many auto-immune conditions ranging from arthritis to autism, but nobody really understood why.  Until now.

This post is about the worms and recent research which has established that it is likely that they work by blocking the potassium channel Kv1.3.

You will have noted that this blog keeps going on about ion channel dysfunctions and autism.  We already know that Cl-, Ca2+ , K+ and Na2+ are all implicated.

When researching calcium channel blockers for autism, one reason I picked Verapamil was that it is also a potassium channel blocker.  My earlier experiments have shown that hypokalemic sensory overload exists in autism, I showed that oral potassium could treat sensory overload.

Hypokalemic Autistic Sensory Overload

 
This blog is (slowly) working its way through the ion channel dysfunctions known to exist in autism.

Well, it appears that Verapamil also blocks Kv1.3.

Block of the lymphocyte K+ channel mKv1.3 by the phenylalkylamine verapamil



Research Down Under

Researchers in Australia have identified the chemicals released by parasitic worms that have the effect of subduing the immune system.  They identified a large family of Stichodactyla helianthus toxin (ShK)–related peptides in parasitic worms, they showed that these peptides acted to inhibit Kv1.3 channels in human T cells.


Abstract

The voltage-gated potassium (Kv) 1.3 channel is widely regarded as a therapeutic target for immunomodulation in autoimmune diseases. ShK-186, a selective inhibitor of Kv1.3 channels, ameliorates autoimmune diseases in rodent models, and human phase 1 trials of this agent in healthy volunteers have been completed. In this study, we identified and characterized a large family of Stichodactyla helianthus toxin (ShK)–related peptides in parasitic worms. Based on phylogenetic analysis, 2 worm peptides were selected for study: AcK1, a 51-residue peptide expressed in the anterior secretory glands of the dog-infecting hookworm Ancylostoma caninum and the human-infecting hookworm Ancylostoma ceylanicum, and BmK1, the C-terminal domain of a metalloprotease from the filarial worm Brugia malayi. These peptides in solution adopt helical structures closely resembling that of ShK. At doses in the nanomolar–micromolar range, they block native Kv1.3 in human T cells and cloned Kv1.3 stably expressed in L929 mouse fibroblasts. They preferentially suppress the proliferation of rat CCR7 effector memory T cells without affecting naive and central memory subsets and inhibit the delayed-type hypersensitivity (DTH) response caused by skin-homing effector memory T cells in rats. Further, they suppress IFNγ production by human T lymphocytes. ShK-related peptides in parasitic worms may contribute to the potential beneficial effects of probiotic parasitic worm therapy in human autoimmune diseases

A less heavy summary is here:-

'Wormpill' could ease autoimmune disease symptoms

  
The researchers noted that Kv1.3 is widely regarded as a therapeutic target for immunomodulation in autoimmune diseases.

So it seems that they have identified the mechanism of action of the worms.

Earlier posts have mentioned intentionally swallowing TSO parasites (Helminthic therapy) for autism and the trials now ongoing by Coronado Biosciences.   Here is part of one post:-

I think that TSO is very interesting.  It is now being developed by Coronado Biosciences as a therapy for several inflammatory conditions including:-

·        Crohn’s disease
·        Ulcerative Colitis
·        Autism

Here is a link to all the clinical trials they are running.

The idea behind TSO is that the parasites have evolved a method of ensuring their survival in their host, by subduing the immune system, so that they are not killed/ejected.  By down-regulating the immune system, they become a therapy for diseases featuring an over active immune system.

This all started a few years ago when one autism Dad figured all this out and tried it on his own son.  Then began the long process of clinical trials, which then ended up with Coronado Biosciences.  The Dad’s website is here.

The Australians have the idea of making their (ShK)–related peptides into a drug therapy.  So no need to swallow those worms after all.


Verapamil or Stichodactyla helianthus toxin (ShK)–related Peptides

Just as the Australians may have trumped Coronado Bioscience with their better-than-a-worm peptide pill, has Verapamil the ability to trump the Ozzies?

We know that Verapamil is neutralizing many allergic reactions affecting autism all over the body.  This appears to be a combination of mast cell stabilization and a possible effect on pancreatic function that reduces GI problems.  But is Verapamil’s inhibitory effect on Kv1.3 also providing a broader immunomodulatory effect as well?  It does indeed look possible.

We would need somebody using TSO worms for autism, to see if Verapamil was effective for them too.  Any volunteers?

Unlike the TSO worms and the ShK peptides, Verapamil is cheap and sitting on the shelf in your local pharmacy.