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).

 

 

Calcium Folinate (Leucovorin) to Prevent as well as Treat Autism?

 

Belgium is famous for many things from chocolate and beer to comic books like Tintin.

  Even the Smurfs are from Belgium.

 

If you want to investigate autism you might need the skills of the most famous fictional Belgian, Hercule Poirot.

Today’s post is about the detective work of Dr Ramaekers from Liège.

Liège is a city in the French-speaking part of Belgium. The northern half of Belgium speak Dutch and southern half speak French. The capital Brussels is officially a bilingual city, but if you do not want to upset an unknown local, the safest language to use is actually English.

Liège used to be a major European centre for steel making.  My elder son tells me that Liège is still famous for making guns.

In 2020 Liège is the European home of Folate receptor antibodies research and more importantly, its treatment.

Outside of Brussels the touristy parts of Belgium include Bruges, Gent and Antwerp, where your French from school is less useful. If you like medieval towns, excellent food and mayonnaise on fries/chips these places are well worth a visit, on a sunny day.   I used to go there on business.

The point of today’s post goes beyond the fact that Dr Ramaekers and Dr Frye have demonstrated that a large sub-group of autism benefit from supplementation with calcium Folinate (Leucovorin).

Ramaekers is looking at Folate Receptor Autoimmunity in the parents, to understand why/how the child developed autism in the first place and then taking the very logical step to prevent future autism.

My elder son is very keen that I master the art/science of preventing future autism, so as to ensure his own children will be neurotypical.

Attempting to prevent future autism will very likely also give some protection against all those "autism-lite conditions", like selective eating, AD(H)D, dyslexia, dyspraxia etc.

At the 2020 Synchrony autism conference, Dr Ramaekers spoke about how several healthy babies have now been born to parents treated with Leucovorin for their Folate Receptor Autoimmunity.  I assume the parents already have at least one child with autism and do not want more.  I thought that was a bold move by Dr Ramaekers. Dr Ramaekers has been publishing research on Folate Receptor Autoimmunity for many years and so I suppose he has the freedom to do this.  In some countries I think you would not be able to do this, or at least talk about it.  Anyway, “dix points Dr Ramaekers”  (ten out of ten).

As with the potential use by mothers of the antioxidant NAC during pregnancy, the mode of action is epigenetic and preventing differentially expressed genes (DEGs), or just call them miss-expressed genes.

In Dr Ramaeker's case he does have a biomarker to identify parents likely to benefit from his autism prevention strategy.  He uses the FRα autoantibody test and so could you.

I have been having an interesting public discussion with Dr Ramaeker's on the online app used for the Synchrony 2020 autism conference. The key point arising is that you can avoid the side effects of using Leucovorin (Calcium Folinate) by slowing increasing the dosage over several weeks.  Here is the relevant part:-

You had one naughty remark concerning the Use of folinic acid causing agression. My response is that folinic acid will increase the production of BH4 which will suddenly increase the synaptic levels of dopamine AND serotonin AND cause temporarily overstimulation of downregulated dopamine AND serotonin receptors. After about 6 weeks will settle down as a new equilibrium will be installeer. So I begin with low dosage folinic acid AND slowly increase at interval of 4 weeks.It was a wonderfull overview about your sons history.

For anyone interested to watch my Bumetanide presentation, that Dr Ramaekers, AJ and Lisa  seem to have enjoyed, here is a link.

https://drive.google.com/file/d/15s_1x01VR2v-iMNpgbsFtt12Ug4xbGTh/view

The paper by Dr Ramaekers below is open access and many people will find it interesting to read the entire paper.  Just skip over any parts that get too complicated.

 

Improving Outcome in Infantile Autism with Folate Receptor Autoimmunity and Nutritional Derangements: A Self-Controlled Trial

Background. In contrast to multiple rare monogenetic abnormalities, a common biomarker among children with infantile autism and their parents is the discovery of serum autoantibodies directed to the folate receptor alpha (FRα) localized at blood-brain and placental barriers, impairing physiologic folate transfer to the brain and fetus. Since outcome after behavioral intervention remains poor, a trial was designed to treat folate receptor alpha (FRα) autoimmunity combined with correction of deficient nutrients due to abnormal feeding habits. 

Methods. All participants with nonsyndromic infantile autism underwent a routine protocol measuring CBC, iron, vitamins, coenzyme Q10, metals, and trace elements. Serum FRα autoantibodies were assessed in patients, their parents, and healthy controls. A self-controlled therapeutic trial treated nutritional derangements with addition of high-dose folinic acid if FRα autoantibodies tested positive. The Childhood Autism Rating Scale (CARS) monitored at baseline and following 2 years of treatment was compared to the CARS of untreated autistic children serving as a reference. 

Results. In this self-controlled trial (82 children; mean age ± SD: 4.4 ± 2.3 years; male:female ratio: 4.8:1), FRα autoantibodies were found in 75.6 % of the children, 34.1 % of mothers, and 29.4 % of fathers versus 3.3 % in healthy controls. Compared to untreated patients with autism (n=84) whose CARS score remained unchanged, a 2-year treatment decreased the initial CARS score from severe (mean ± SD: 41.34 ± 6.47) to moderate or mild autism (mean ± SD: 34.35 ± 6.25; paired t-test p<0.0001), achieving complete recovery in 17/82 children (20.7 %). Prognosis became less favorable with the finding of higher FRα autoantibody titers, positive maternal FRα autoantibodies, or FRα antibodies in both parents. 

Conclusions. Correction of nutritional deficiencies combined with high-dose folinic acid improved outcome for autism, although the trend of a poor prognosis due to maternal FRα antibodies or FRα antibodies in both parents may warrant folinic acid intervention before conception and during pregnancy.

 

 

The treatment protocol for the self-controlled treatment trial based upon abnormal biochemical findings and FRα autoantibodies.

Abnormal biomarker Daily oral supplement dosage Zinc deficiency 0.15-0.25 mg/kg zinc-sulfate Selenium deficiency 3-5 µg/kg sodium-selenite Manganese deficiency 5-10 mg/kg Vitamin C, 20 IU/kg Vitamine E, with 1 coffespoon Soya oil at night. Manganese excess idem Heavy metal excess (Cu, Al, Hg, Pb) idem Raised copper/zinc ratio idem Bèta-carotene excess idem; limit foods rich in bèta-carotene Vitamin A deficiency 600-1500 µg Vitamin D (25-hydroxy-D) 10 µg or 400 IU Vitamin C deficiency 5-10 mg/kg Vitamine C (maximal 500mg) Ubiquinon-10 deficiency 2 mg/kg co-enzyme Q10 Vitamin E deficiency 20 IU/kg Gamma-Tocopherole deficiency 1 coffeespoon soya, corn or sesame oil Bèta-carotene deficiency Consume tomato or carot juices Serum folate deficiency 0.5 mg/kg folinic acid RBC folate deficiency 0.5 mg/kg folinic acid Apolipoproteine B deficiency Supplement vitamins A D E, and vitamine K in case of secondary coagulation disorder FR-alpha antibodies Start with 0.5-1 mg/kg folinic acid daily;   Increase to 2 mg/kg daily without a clinical response after six months. Maximum daily dose 50 mg.

 

 

In the study they used the CARS rating scale to measure the severity of autism.

A score 30 and above 30 means autism.  37 and above means severe autism.

The results do look good.  This was not a study with a placebo group for comparison.

Blue is before therapy and orange is after therapy.

 

 

The upper figure (a) shows the plotted CARS with age for 84 untreated patients. The middle figure (b) shows the effect of treatment among 82 treated patients (blue bars represent CARS at baseline and orange bars the CARS after two years treatment). Figure (c) represents the treatment results among different groups with FR autoantibodies in the child (K), mother (M), or father (P).

 

 

Our self-controlled treatment trial showed that the presence of maternal FRα autoantibodies or FRα antibodies in both parents tended to be associated with a higher initial baseline CARS score among affected children with autism. Thus, this may explain that the final result and change in CARS score following 2-year treatment was less pronounced as compared to all other groups, although the small number of patients within each group did not allow a profound statistical analysis. These issues will be clarified when more patients will be included into similar treatment trials. Our findings in a minority of 7 out of 68 families (10%) identified no FRα autoantibodies in the children whereas FRα antibodies could only be detected in the mother (N=5), father (N=1), or both parents (N=1). Although feeding and nutrient problems for each child have to be taken into account, this finding suggests that parental FRα antibodies may impair folate transport into oocytes and spermatozoides and also block sufficient folate transport across the placental barrier to the embryo and fetus. Because an adequate folate pool is essential for purine and pyrimidine synthesis, and for mediating epigenetic mechanisms involving DNA methylation and histone modification, the initial embryonic development and subsequent stages of neurodevelopment will rely heavily on availability of adequate folate. Therefore, the risk of autism with its poor prognosis in the offspring associated with parental FRα antibodies warrants FRα testing among future parents followed by folinic acid intervention before conception and during pregnancy.

The common feeding disturbances associated with autism may provoke oxidative stress due to altered nutritional states where elevated metals (copper, manganese) or beta-carotene act as prooxidants through induction of Fenton chemistry. Nutritional deficiencies of radical scavenging vitamins (vitamins A, C, E, and gamma-tocopherol) as well as metals and trace elements (copper, zinc, manganese, and selenium), being cofactors of antioxidative enzymes, predispose to failing antioxidant defences. Moderate apolipoprotein B deficiency has been encountered in a significant number of autistic subjects and leads to deficient liposoluble vitamins A, D, E, and K. Deficiency of a number of vitamins and coenzyme Q10 necessary for mitochondrial metabolism, will result in mitochondrial dysfunction. Thus, oxidative stress in the brain due to mitochondrial dysfunction, elevated prooxidants, or deficient antioxidants on the one hand and FRα autoimmunity on the other hand, represent two independent variables at the basis of autism where correction of each variable showed a clinical response with a decline in the CARS score. Therefore, in addition to treatment for FRα autoimmunity [9, 10, 29], specific supplements are required to correct nutritional deficiencies in order to ameliorate intermediary metabolism and to neutralize abundant reactive oxygen species (ROS) deranging brain metabolism and function. As stated above, it appears from our findings in this study that the group of patients, where FRα antibodies tested negative in the child and its parents, benefitted only through correction of nutritional derangements as their CARS score dropped significantly.

In our study we also detected deficiencies of serum and red blood cell folate in 18.3 % of all patients. In vitro studies have supported the concept of an existing link between oxidative stress and deranged folate homeostasis. In a previous study we found that the generation of superoxide anions in vitro catabolizes 5-methyl-tetrahydrofolate by 75% within one hour, which can be prevented through preincubation with the radical scavenger ascorbic acid [26]. This study also found that KB-cells in culture exposed to superoxide anions and hydrogen peroxide reduces cellular folate incorporation mediated by FRα or RFC1 transport mechanisms. Thus transmembrane folate passage mediated by these transporters at the placenta and choroid plexus is expected to be impaired in the presence of ROS and predisposes to intrauterine folate deficiency and cerebral folate deficiency.

The consequences of folate deficiency affecting brain development may be more prominent in autistic children from mothers with folate deficiency or the presence of maternal FRα autoantibodies during pregnancy. Our finding of a higher initial baseline CARS score and less favorable outcome in these children confirms this hypothesis. In summary, the treatment response will be influenced in a negative fashion by the presence of maternal FRα autoantibodies, by late-onset treatment associated with a higher initial CARS score and in the event of elevated antibody titers. Paternal FRα antibodies may also influence the outcome and need to be further investigated, because we only identified one family.

 

5. Conclusion

In the pathogenesis of low-functioning autism, feeding disturbances predisposing to oxidative stress and acquisition of folate receptor autoantibodies during the pre- or postnatal period appear to play an important role by affecting intermediary metabolism and potentially deranging epigenetic control mechanisms. Early detection and appropriate therapeutic intervention is postulated to reverse core features and improve outcome.

 

 

Conclusion

Today’s paper showed several interesting things:- 

·        Correcting the effects of very poor diet can have a dramatic benefit on autism, regardless of folate status.

·        Folate receptor problems are very common in autism.  FRα autoantibodies were found in three quarters of children with autism and a third of their mothers and fathers, versus just 3 % in healthy controls.

·        A trial of Calcium Folinate (Leucovorin) for anyone with autism looks like a “no-brainer” but, as Dr Ramaekers cautions, mega dose folate might be unwise in the 25% of autism who do not have FRα autoantibodies.  

Note that in the study, prognosis became less favorable with the finding of higher FRα autoantibody levels, maternal FRα autoantibodies, or FRα antibodies in both parents.

·        Couples/parents who want (more) children, but want to avoid autism, should consider first taking the FRα autoantibody test

http://iliadneuro.com/

if you get a positive result, you might contact our man in Liège.

·       Generic Calcium Folinate (Leucovorin) is cheap in most of the world.  As usual, the exception is the United States. 

     I will have to write a post on prenatal bumetanide to prevent autism. Dr Ben Ari did mention again at the Synchrony event the potential for this therapy.  It seems that the oxytocin released by the mother during delivery not only helps to trigger the developmental GABA switch that forces neurons to transition from immature to mature over the first couple of weeks after birth, but it also causes a one time shock reduction in chloride during delivery (this shock may indeeed be the GABA switch trigger).  It seems that the fragile brain is given protection during delivery, with GABA switching from the fetal excitatory state to one of extreme inhibition, just for birthing.  This protective sudden drop in chloride levels does not occur in autism models and likely not in human autism either. The logic would be to give the mother bumetanide for 2 weeks before her delivery date.  This would protect the baby's brain during birth and hopefully help ensure the GABA switch occurs and the child develops normally.

 

I

 

Averting Autism - Antenatal Antioxidants? But Male, Female or Both?

 

 Salem College

 

Today’s post is the first of two new ones about preventing/minimizing future autism.  The second post will be about Dr Ramaekers’ idea of using Calcium Folinate, which he has already put into use in human parents seeking to avoid autism in their next child. 

Before we start, I should point out that while readers of this blog, and it seems Dr Ramaekers, likely wish that autism and its symptoms did not exist, there are some people, well paid to research autism, who think autism is a good thing. I really do wonder why such people receive any public funding and wonder what kind of University would employ such people. It is like researching deafness, but not wanting to treat it - better they stay home.

https://www.sciencedaily.com/releases/2020/08/200824091958.htm

Simon Baron-Cohen, PhD, Director of the Autism Research Centre at Cambridge, who co-led the study, added, "Some people may be worried that basic research into differences in the autistic and typical brain prenatally may be intended to 'prevent,' 'eradicate,' or 'cure' autism. This is not our motivation, and we are outspoken in our values in standing up against eugenics and in valuing neurodiversity. Such studies will lead to a better understanding of brain development in both autistic and typical individuals."

Even more odd is that Baron-Cohen's sister had a rare mutation of the GNAQ gene that led to intellectual disability and a reduced lifespan. Why would you not want to treat/prevent that?  Treating your sister would not have meant you did not value her, it would have been another sign that you loved her. 

A positive example is another autism researcher, Manuel Casanova, and his family, who set up a research effort for people who have a disorder related to the gene NGLY1.  Sadly, Manuel's grandson passed away, but the research goes on.   

If you can escape from intellectual disability, someone should make it happen.  That someone might be you.

 

I must admit I had never heard of Salem College.  It is an all-female college in Winston-Salem, North Carolina.  It is the source of another idea to avert autism, this time treating the future father with an anti-oxidant like NAC.  NAC was already on my list for future mothers.  When it comes to autism, it looks like little Salem College is going to be more useful than stuffy old Cambridge University.

I am rather surprised there still are all female colleges, but in the US, there are many.

My mother went to an all-female college at Cambridge University, back then they had no mixed colleges.  Only after 1948 could women even receive a degree at the end of their studies. Cambridge University still has three all-female colleges.

Clearly male post-conception antioxidant supplementation is not going to help.

We have already seen in the research that the future father can damage the DNA he passes on to his offspring.  This was done via epigenetic tags on his DNA caused by things like recreational drug use, or smoking tobacco.

The author of today’s paper look’s exclusively at autism risk from the father, but exactly the same therapy during pregnancy can reduce risk from the mother.  The maternal immune activation model is one of the most studied in autism. We also know that emotional stress during pregnancy increases autism risk.  Emotional stress leads to oxidative stress.

The only issue I had with this preventative approach is whether there are any negative effects from antioxidants during pregnancy.  There may well be none, since the body just adjusts production of its own antioxidants.

There was an interesting experiment I mentioned a while back about giving antioxidant or “detox” juices to healthy young people.  The anti-oxidants from the fruits just made the body reduce its own production of GSH/glutathione, so the net result of the detox juice was actually negative.  People in oxidative stress benefit from anti-oxidant therapy, everyone else is wasting their money.

There are highly conflicting reports as to whether autism tends to come from the mother’s half of the child’s DNA or from the father’s half.  In reality it does not matter, it can from either, both or neither.  What is important is to take whatever simple safe steps you can to avert future autism. 

Future parents taking NAC and Calcium Folinate, might as well join the idea of keeping pets at home during pregnancy to get exposure to the evolutionarily expected bacteria that are needed to calibrate the immune system of the fetus/baby. Humans have been living with dogs, and very importantly their bacteria, for 11,000 years.  Only very recently did humans come up with the idea of trying to kill 99.9% of bacteria in their homes. 

Dogs are humans' oldest companions, DNA shows

I really do not see anyone doing a placebo controlled clinical trial on any of this.  Nobody who agrees to participate will accept the risk of being in the placebo group.  You would have to create a control group out of people who did not want to join the trial.  The people who join the trial are self-selected and are more likely to be health conscious, or have a family history of autism or dys-something else.

Male preconception antioxidant supplementation may lower autism risk: a call for studies

Current research indicates that a sizable number of autism spectrum disorder (ASD) cases arise from de novo mutations (DNMs) occurring within the paternal germline, usually in an age-dependent manner. Andrologists have reported that somatic cells and gametes share the same pathologies that generate these DNMs—specifically, DNA hypomethylation caused by oxidative nucleoside base damage. Because many ASD researchers seek to identify genetic risk factors, teams are developing methods of assessing aberrant DNA patterns, such as parental gonadal mosaicism. Several studies propose antioxidant supplementation as a strategy to lower autism risk, and/or suggest connections between childhood neurodevelopmental disorders such as autism and paternally-derived DNMs. Actual data, however, are currently not available to determine whether male preconception antioxidant supplementation effectively lowers autism risk. The purpose of this paper is to (1) explore the mechanisms causing DNMs, specifically DNA hypomethylation; (2) explain how antioxidant supplementation may lower the risk of having a child with ASD; and, (3) advocate for the implementation of large prospective studies testing (2). These studies may very well find that male preconception supplementation with antioxidants prevents neurodevelopmental disorders in offspring, in much the same way that female prenatal consumption of folate was found to decrease the risk of birth defects. If this is indeed the case, the alarming rise in autism prevalence rates of the past few decades will slow—or even cease—upon the initiation of public awareness campaigns.

  

Antenatal antioxidants to avert autism?

Paternally derived de novo mutations (DNMs) caused by oxidative stress (OS) have been implicated in the development of autism spectrum disorders (ASDs). Whether preconception antioxidant supplementation can reduce the incidence of ASDs by reducing OS is an area of uncertainty and potentially important future scientific investigation.

The recently completed double blind, multicenter, randomized controlled Males, Antioxidants, and Infertility (MOXI) trial by the Reproductive Medicine Network (RMN), funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), investigated whether antioxidants improve male fertility, as measured by semen parameters and sperm DNA integrity at 3 months and pregnancy by 6 months of treatment [11]. The RMN investigators found that antioxidant treatment of the male partner does not improve semen parameters, sperm DNA integrity, or in vivo pregnancy rates in couples with male factor infertility, prompting the question whether antioxidant therapy should no longer be routinely recommended for infertile men [12]. It would be intriguing to evaluate the offspring from the participant couples of the MOXI trial for ASD. However, with only 13 live births in the antioxidant group and 21 live births in the placebo arm, the study would be vastly underpowered to demonstrate a benefit of antioxidants in the prevention of a condition with an incidence of 1 in 54 children.

The next post is about Dr Ramaeker's clinical trial of calcium folinate in children with autism and his comments about their parents and future siblings.