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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.









17 comments:

  1. Those who remember B. Fragilis for autism, it has come in the spotlight again, this time not so nice:

    Researchers Discover New Link Between Autoimmune Diseases and a Gut Bacterium
    https://www.infectioncontroltoday.com/immune-system/researchers-discover-new-link-between-autoimmune-diseases-and-gut-bacterium

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    Replies
    1. Very interesting Aspie1983 and a timely reminder that defining bacteria as either good or bad is very unhelpful and simplistic.

      Gut bacteria is a subject very much in fashion, but it is early days when it comes to therapeutics. Many people seem to make things worse rather than better, when they use probiotics.

      Some people do indeed benefit from currently available products. VSL#3 looks particularly good for some people with severe IBS/IBD.

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  2. I know a father from France who used TSO for his kid, but his kid is overall not having a lot of progress. Also, on the topic of microbiom, the Taymount clinic from London finally has a european locatiom doing FMT for kids - in Bratislava. Its 2500 and I am currently considering whether this is worth the money for us right now. I think in the end I will do it because I am currently cleaning leftover options from the table, but she never had all that much GI problems. My daughter and I tried the probiotic you mentioned, Biogaia, and we were both very sad forna few days. A coincidence? I don’t know. Anyway, for people considering this, I know that overall FMT and autism have had a great run in the US before the FDA decided this was a real TRANSPLANT, requiring the same process and clinic as an organ transplant. Yes, I know.

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  3. Here is some Parkinson's research that may be very relevant to autism, especially as it relates to a recent post concerning the NLRP3 inflammasome on this blog:

    Peter's Blog Post:

    https://epiphanyasd.blogspot.com/2018/09/ketones-and-autism-part-4-inflammation.html

    Press Release:

    https://www.sciencedaily.com/releases/2018/10/181031141520.htm

    Paper:

    http://stm.sciencemag.org/content/10/465/eaah4066

    In this particular paper, they showed that attenuating the NLRP3 inflammasome via a small molecule inhibitor given orally (I have no idea if this is safe for humans or not) reduced various Parkinsonism symptoms, as well as reduced the aggregation of alpha-synuclein proteins which is though to be one of the main drivers of nigrostriatal dopamine neuron degeneration.

    The small molecule NLRP3 inhibitor is called MCC950 and is discussed extensively in Peter's recent posting which I did not realize was intended to be a commercial arthritis drug by Pfizer until rereading his blog post. Sadly, it was also developed over two decades ago which unfortunately means there is likely little patent protection on it anymore, and therefore little impetus to put the resources into making it available commercially (at least in the United States).

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  4. Here is some very interesting research that is somewhat relevant to this topic with regards to TH1 and TH17 signaling (though it is not about TSO):

    Press Release:

    https://www.sciencedaily.com/releases/2018/11/181101133931.htm

    Paper:

    https://www.cell.com/cell/fulltext/S0092-8674(18)31309-6?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867418313096%3Fshowall%3Dtrue

    This research concerns glutamine metabolism and its effects on TH1 and TH17 immune cells. The research was inspired via cancer research that concerns the mechanism of how inhibiting glutamine metabolism via inhibiting the enzyme glutaminase, helps reduce the growth of some types of cancer cells, but fails at others. What they found was very interesting in that glutamine metabolism is pro-TH17 while anti-TH1 which is a very interesting finding as it relates to autoimmune disorders like rheumatoid arthritis, but also autism where there is a lot of research showing TH1/TH17 interactions playing a big role (Peter has covered this topic extensively).

    Glutamine also was shown to enhance mTORC1 signaling (probably bad in most autism), and in a separate paper I posted in the comments section several pages back on this blog, it showed that the ratio of BCAA's to several other amino acids, in particular glutamine, was low (i.e. too much glutamine relative to BCAA's is correlated with autism symptoms):

    https://epiphanyasd.blogspot.com/2018/09/ketones-and-autism-part-4-inflammation.html?showComment=1536298446069#c7621199896891606272

    Also, simply restricting Glutamine from the diet is pretty much impossible as Glutamine is the most abundant amino acid in muscle tissue, let alone many other tissues in the body. Glutamine weakly competes with BCAA's at the blood-brain barrier, though there are multiple methods of transport for glutamine to get in the brain. On top of that, glutamine is constantly recycled into GABA, Aspartate, and Glutamate over and over again in the brain, so the most practical intervention for exploiting this research would likely be a glutaminase inhibitor as the researchers in this study have shown and suggested.

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  5. Peter,
    Now that we are on the subject of the immunesystem, I want to get my blood drawn or however I can get my immunesystem checked, I know theres IGg, IGm, IGe? Im clueless what I should get checked for. Also im assuming these are bloodtests?

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    Replies
    1. Aspie1983, there are hundreds of "standard" tests in immunology. Here is a good link to see what can get tested in one European centre.

      https://www.ouh.nhs.uk/immunology/diagnostic-tests/default.aspx

      For autism you would really want to test the level of specific cytokines, both pro and anti-inflammatory. But there really isn't anyone to interpret the results for you.

      I expect in the US they have hundreds more tests available and so that will be the first place to see some progress in defining sub-groups based on biomarkers.


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    2. I would also test IGG subclasses. I also second the cytokines. For us they are quite simply the only tool we need to check how our kid is doing. It always correlates with behaviour.

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    3. Tatjana- Do you get an order for your tests, do you order them yourself? I am curious because I have a difficult time finding a provider to look into immune system function.

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    4. I have the luxury of living in Europe where you can order everything yourself if you are a bit resourceful. You pay for it by yourself too. We do the cytokines through r.e.d. labs and the igg subclasses we did on italy through our autism doctor, at a university clinic for children. we later repeated the test locally but the results were nonsensical so I doubt the quality of them. there is a very good autism doctor in italy who can sort you out as far as access to labs goes and I think that in broader terms this is not as expensive as one might think.

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    5. Hi Tatjana,
      Thank you for your information, maybe I should contact my previous psychiater who works through one of the leading autism research groups here in holland. I suspect he is more open to the idea and might help me get a test done.
      My current psych (through a regular institute) does allow me try new medicines so thats awesome, Im getting donepezil for example in around 2-3 weeks and will see how I respond to that.
      If that isnt a success I will 100% try bumetanide (I have been scared of it somewhat because it can elevate urea).

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    6. Aspie1983,
      I am not sure where you live but in the US I just found Cyrex Labs- the different arrays can be helpful.

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    7. Im from the Netherlands mate (where weed also obviously is legalized), I will try find out if insurance fully covers the blood tests and other ways to test my immune function (under the assumptions my psych gives me the go signal to get tested).

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    8. Aspie, literally everybody who wants to know, knows by now that most psychiatric disorders have to do with inflammation of the brain. So your old psychiatrist might be inclined perhaps to look at it that way. Bumetanide ...you can counteract the elevated urea by eating less meat.

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    9. but since r.e.d. labs are very close to where you are you can just call them and ask them whether theyvwould let you order or otherwise which dcotors they usually work with in your area.

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  6. Hi Peter, Friends, and Community,

    Hope everyone is doing well!

    I wanted to share two really interesting pieces of news that have come out very recently:

    1. 'Master key' gene has links to both ASD and schizophrenia
    Mice lacking MIR-137 show ASD-ish phenotype + increased Pde10a

    https://www.sciencedaily.com/releases/2018/11/181105122540.htm

    2. Unraveling a genetic network linked to autism

    https://www.sciencedaily.com/releases/2018/11/181102131942.htm

    Hope everyone finds the above interesting, and to me, we really seem to be moving in the right direction.

    I have a good feeling that some exciting news is right around the corner.

    Have a great night everyone!

    AJ

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    Replies
    1. For your first link about Pde10a, the researchers used a drug called Papaverine which was discovered by the Merck family around 170 years ago. In the last 10 years there have been several studies looking at pde10a inhibition for schizophrenia, though from what I have read it's utility is complicated in that for the therapy to work properly, dopamine signaling needs to be balanced between the direct and indirect pathways in the striatum. Nevertheless, Papaverine might as well be an ancient drug so a lot is known about its safety profile, though I am not sure it would.be recommended for children anytime soon due to its many reported side effects.

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