Consequences of folate deficiency – treated by immunomodulators (Infliximab, IVIG, Propes and Inflamafertin) and the relevance of mutations in MTHFR, MTR, and MTRR genes in identifying those at risk. Plus the effect of rTMS and tDCS on milder autism

 

Today’s post returns to folate deficiency, but before that a quick mention of magnetic/electrical brain stimulation therapies for autism without impaired cognition.

I encountered a new term IC-ASD. It stands for intellectually capable autism spectrum disorder. Most people with autism these days seem to have IC-ASD. Some struggle and some do not.

 

The effects of rTMS and tDCS on repetitive/stereotypical behaviors,cognitive/executive functions in intellectually capable children and young adults with autism spectrum disorder: A systematic review and meta-analysis of randomized controlled trials

 

Objective

This study aims to evaluate the efficacy of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) on repetitive/stereotypical behaviors and cognitive/executive functions in children and young adults with intellectually capable autism spectrum disorder (IC-ASD).

Methods

Literature searches across PubMed, Web of Science, Cochrane Library, Embase, and Scopus were performed to identify randomized controlled trials (RCTs) evaluating the efficacy of rTMS and tDCS in children and young adults with IC-ASD. The search encompassed articles published up to April 25, 2025. The standardized mean difference (SMD) with 95 % confidence intervals (CI) was calculated and pooled. Sensitivity and subgroup analyses were conducted to assess potential sources of heterogeneity and refine the robustness of the findings.

Results

This meta-analysis included 18 RCTs involving 813 participants. Compared with sham interventions, tDCS demonstrated significant improvements in social communication, repetitive and stereotypical behaviors, cognitive and executive functions among individuals with IC-ASD (e.g., Social Responsiveness Scale: SMD = –0.48; 95 % CI: –0.75 to –0.22; p < 0.01). Similarly, rTMS improved social communication, repetitive and abnormal behaviors (Social Responsiveness Scale: SMD = –0.21; 95 % CI: –0.42 to –0.00; p < 0.05; Repetitive Behavior Scale-Revised: SMD = –0.62; 95 % CI: –1.17 to –0.07; p = 0.04; Aberrant Behavior Checklist: SMD = –0.53; 95 % CI: –0.79 to –0.26; p < 0.01). No significant heterogeneity was observed across studies.

Conclusion

tDCS and rTMS may enhance cognitive and executive functions and reduce repetitive behaviors in children and young adults with IC-ASD. However, these findings require careful interpretation due to the limited high-quality studies and variability in treatment protocols. Future research should prioritize the development of standardized protocols to address inconsistencies in stimulation parameters (including frequency, intensity, and duration) and core outcome sets. Additionally, larger-scale, rigorously blinded multi-center RCTs are necessary to accurately evaluate the clinical efficacy and applicability of these neuromodulation techniques in these populations.

 

rTMS and tDCS look like interesting non-pharmaceutical options for those with milder types of autism. How well they work in those with lower cognitive function is not addressed.

 

Back to Folate Deficiency

Stephen recently highlighted a Chinese study that looked at the relevance of mutations in the genes MTHFR, MTR, and MTRR to try and identify those most at risk of folate deficiency.

I also highlight research into treating some of the downstream consequences that occur when folate metabolism is impaired. The lack of folate disrupts the immune system causing anomalies such as low NK cells, low NKT cells, high TNF-alpha.

Immunodeficiency (Low NK and NKT cells): The deficiency in these crucial innate immune cells means the body's ability to fight off infections (particularly opportunistic ones) and perform immune surveillance (e.g., against abnormal cells) is compromised. This immunosuppression is a direct consequence of the impaired cell proliferation due to the folate cycle defect.

Systemic Inflammation (High TNF-alpha): Despite the low numbers of certain immune cells, there can be an overproduction of pro-inflammatory cytokines like TNF-alpha. This leads to chronic systemic inflammation. This phenomenon is often referred to as hypercytokinemia.

Beyond TNF-alpha, you might expect a possible overproduction of:

• Interleukin-1 beta (IL-1β): This is a potent pro-inflammatory cytokine involved in various immune responses and neuroinflammation.
• Interleukin-6 (IL-6): Another major pro-inflammatory cytokine that plays a role in systemic inflammation and can affect brain development and function.
• Interferon-gamma (IFN-γ): This is a key cytokine in Th1 immune responses and is also pro-inflammatory.

 

The recent Chinese study concludes that high-dose folinic acid appears to be a promising intervention for children with autism. Its efficacy is notably associated with specific folate metabolism gene polymorphisms. The researchers suggest that high-dose folinic acid may help to improve neurodevelopmental outcomes by alleviating the folate metabolism abnormalities caused by single or combined mutations in these genes.

This research indicates that providing a metabolically active form of folate (folinic acid, calcium folinate, leucovorin etc) can be a direct approach to address the underlying metabolic challenges in a subset of people with autism who have specific genetic predispositions related to folate metabolism. Children with MTHFR A1298C or MTRR A66G mutations showed greater improvements in various developmental domains compared to those with the standard versions.

The intervention group demonstrated significantly greater improvements in social reciprocity compared to the control group.

No significant adverse effects were observed during the intervention period.

 

How does this fit in with US research into brain folate deficiency in autism

US researchers consider an autoimmune mechanism where the body produces antibodies that specifically target the Folate Receptor Alpha (FRα). FRα is a crucial protein responsible for transporting folate across the blood-brain barrier (and into other cells).

When these antibodies bind to FRα, they block or interfere with the normal transport of folate into the cells, particularly into the brain. This results in Cerebral Folate Deficiency (CFD), where folate levels in the cerebrospinal fluid are low, despite potentially normal folate levels in the blood.

US research indicates that FRAAs are prevalent in a significant percentage of children with ASD (up to 70% in some studies) and are associated with specific physiological and behavioral characteristics.

Treatment with folinic acid/ leucovorin has been shown to be effective in many children with autism who are positive for FRAAs, improving symptoms like communication, irritability, and stereotypical behaviors. It is believed that high doses of folinic acid can overcome the transport blockade caused by the antibodies

The US and Chinese research avenues complement each other by identifying different, but potentially converging, pathways that lead to folate dysfunction in autism, both of which demonstrate the therapeutic potential of folinic acid.

Here is the Chinese paper: 

Safety and Efficacy of High-Dose Folinic Acid in Children with Autism: The Impact of Folate Metabolism Gene Polymorphisms

Background/Objectives: Research on the safety and efficacy of high-dose folinic acid in Chinese children with autism spectrum disorder (ASD) is limited, and the impact of folate metabolism gene polymorphisms on its efficacy remains unclear. This trial aimed to evaluate the safety and efficacy of high-dose folinic acid intervention in Chinese children with ASD and explore the association between folate metabolism gene polymorphisms and efficacy. Methods: A 12-week randomized clinical trial was conducted, including 80 eligible children with ASD, randomly assigned to an intervention group (n = 50) or a control group (n = 30). The intervention group was administered folinic acid (2 mg/kg/day, max 50 mg/day) in two divided doses. Efficacy was measured using the Psycho-Educational Profile, Third Edition (PEP-3) at baseline and 12 weeks by two trained professionals blind to the group assignments. Methylenetetrahydrofolate reductase (MTHFR C677T, MTHFR A1298C), methionine synthase (MTR A2756G), and methionine synthase reductase (MTRR A66G) were genotyped by the gold standard methods in the intervention group. Results: 49 participants in the intervention group and 27 in the control group completed this trial. Both groups showed improvements from baseline to 12 weeks across most outcome measures. The intervention group demonstrated significantly greater improvements in social reciprocity compared to the control group. Children with MTHFR A1298C or MTRR A66G mutations demonstrated greater improvements in various developmental domains than wild type. Folinic acid may be more effective in certain genotype combinations, such as MTHFR C677T and A1298C. No significant adverse effects were observed during the intervention. Conclusions: High-dose folinic acid may be a promising intervention for children with ASD, and its efficacy is associated with folate metabolism gene polymorphisms. High-dose folinic acid intervention may promote better neurodevelopmental outcomes by alleviating folate metabolism abnormalities caused by single or combined mutations in folate metabolism genes.

 

Treating the downstream consequences of low brain folate

Today’s next papers highlight Infliximab, IVIG, Propes, and Inflamafertin as immunomodulatory therapies that target the downstream consequences of folate deficiency; they do not address or improve the underlying lack of folate.

Folate Deficiency in the Brain: This means there is an inherent problem in the body's ability to process or utilize folate, even if dietary intake is sufficient. It is often due to mutations in genes encoding enzymes of the folate cycle (like MTHFR) or transporters. This leads to issues with DNA synthesis, cell proliferation, and methylation, impacting various systems, including the immune system.

 

Infliximab

Infliximab is a TNF-alpha inhibitor. It blocks the activity of TNF-alpha, a key pro-inflammatory cytokine.

It does not put more folate into the system or fix how folate is metabolized. It is like putting out a fire (inflammation) that was started because of a broken electrical wire (folate deficiency's impact on immunity).

 

IVIG (Intravenous Immunoglobulin)

IVIG is a broad-acting immunomodulatory therapy composed of pooled antibodies from thousands of healthy donors. Its mechanisms are complex and include neutralizing autoantibodies, blocking Fc receptors, modulating cytokine production, affecting T and B cell function, and influencing complement activation.

IVIG aims to rebalance a dysregulated immune system, reduce inflammation, and sometimes provide passive immunity. It is like resetting an overactive or misdirected immune alarm system. The effect may not last.

 

Propes

Propes contains alpha- and beta-defensins and has a "pronounced immunoactivating and lymphoproliferative effect." It directly stimulates the growth and activity of immune cells like NK and NKT cells. It directly addresses the numbers and activity of NK and NKT cells that are deficient due to the folate cycle problem. It makes the existing cells (or promotes the creation of new ones) work better, despite the underlying folate issue.

 

Inflamafertin

This drug, containing alarmines and adrenomedulin of placental origin, has "pronounced anti-inflammatory and immunomodulatory effects mediated by the induction of interleukin 10 synthesis." Its role is to temper the immune activation  and ensure a more balanced, anti-inflammatory environment.

 

In summary

These therapies are all symptomatic or compensatory treatments for the consequences of genetic folate deficiency on the immune system and the body. They address the resulting immunodeficiency, inflammation, and associated clinical symptoms (like behavioral issues or opportunistic infections).

 

They do not:

• Add more folate to the body (like folic acid or L-methylfolate supplementation would).
• Correct the genetic defect that causes the folate cycle deficiency.
• Improve the body's intrinsic ability to metabolize folate.

Genetic deficiency in the folate cycle disrupts fundamental cellular processes required for the normal development, proliferation, and function of NK and NKT cells, leading to their deficiency in affected children. This deficiency, in turn, contributes to the complex immune dysregulation often seen in autism.

 

Key Findings on NK Cells:

• Initial Deficiency: A significant number of children in the study group (53 patients) had an initial deficiency of NK cells.
• Response to Immunotherapy:
• During the 3-month course of Propes and Inflamafertin, the average number of NK cells in the blood almost doubled.
• NK cell counts reached the lower limit of normal in 74% (39 out of 53) of the patients with a deficiency.
• There was a strong statistical link between the immunotherapy and NK cell normalization.
• Sustainability: A notable finding was that the NK cell numbers returned to almost their initial level within 2 months after the immunotherapy was stopped. This suggests that the effect on NK cells might be temporary and dependent on continuous treatment.

 

Key Findings on NKT Cells:

• Initial Deficiency: A larger proportion of children in the study group (87 patients) had an initial deficiency of NKT cells.
• Response to Immunotherapy:
• The average number of NKT cells in the blood increased by half during the 3-month immunotherapy course.
• NKT cell counts were normalized in 89% (78 out of 87) of the patients with a deficiency.
• There was an even stronger statistical link between the immunotherapy and NKT cell normalization compared to NK cells.
• Sustainability: Importantly, the NKT cell numbers continued to grow for an additional 2 months after the discontinuation of the immunotropic drugs. This suggests a more sustained and potentially longer-lasting effect on NKT cells.

Overall Conclusions from the Study:

• Combination immunotherapy with Propes and Inflamafertin is presented as an effective treatment strategy for the immunodeficiency (specifically NK and NKT cell deficiency) found in children with ASD linked to genetic folate deficiency.
• Both biological drugs were able to normalize the reduced numbers of NK and NKT cells during the 3-month treatment period.
• The study highlights that the effect on NKT cells was more frequent, stronger, and more lasting compared to the effect on NK lymphocytes.

 

The research papers:

EFFICACY OF INFLIXIMAB IN AUTISM SPECTRUM DISORDERS IN CHILDREN ASSOCIATED WITH GENETIC DEFICIENCY OF THE FOLATE CYCLE

 The notion of systemic inflammation in autism spectrum disorders in children has been established. A recent meta-analysis of randomized controlled trials published in 2019, which included a systematic review of 25 case-control studies, suggests an association between genetic deficiency of the folate cycle and autism spectrum disorders in children [18]. This evidence is consistent with an earlier meta-analysis of randomized controlled trials from 2013, which included data from 8 studies [17]. The encephalopathy that develops in children with genetic deficiency of the folate cycle and manifests as autism spectrum disorders is associated with oxidative stress. The reason for the latter can be seen in the suppression of the immune system with the development of a special form of immunodeficiency, which is based on the deficiency of natural killers, natural killer T lymphocytes and CD8 +  cytotoxic T cells [11]. Immunodeficiency mediates all three known mechanisms of brain damage in children with genetic deficiency of the folate cycle, namely the development of opportunistic infections [2, 15], autoimmune reactions against neuronal antigens [3, 6] and manifestations of systemic inflammation, which is based on the phenomenon of hypercytokinemia [13, 20]. Children with autism spectrum disorders have been shown to have overproduction of several proinflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha), interleukin-1beta, and interleukin-6

In SG, there was a pronounced positive dynamics in the direction of hyperactivity, hyperexcitability and stereotyped behavior, but no significant effect was noted on the stability of eye contact and the development of expressive-receptive language, while in CG some positive changes were achieved specifically in terms of expressive language and the level of eye contact, which indicates different points of action of infliximab and specialized educational programs (Table 11.1). The psychotropic effect obtained with infliximab differs from that of intravenous immunoglobulin, which has also demonstrated clinical efficacy in ASD associated with GDFC [10, 12]. The changes induced by infliximab are more pronounced and develop in a shorter time frame, but they are significantly narrower in terms of the spectrum of positive psychotropic effects compared to high-dose immunoglobulin therapy, which has a total modifying effect on the psyche of such children.

Materials and methods. This prospective controlled single-center non-randomized clinical study included 225 children diagnosed with autism spectrum disorders associated with genetic deficiency of the folate cycle. The diagnosis of autism spectrum disorders was made by psychiatrists from regional hospitals or specialized departments according to DSM–IV–TR (Diagnostic and Statistical Manual of mental disorders) and ICD–10 criteria. Children were recruited into the study group (SG) in 2019–2020. These were patients from different regions of Ukraine aged 2 to 9 years, in whom elevated serum TNF-alpha concentrations were observed. As is known, the phenotype of genetic deficiency of the folate cycle includes 5 main syndromes: autism spectrum disorders, intestinal syndrome (persistent enteritis/colitis) [7], PANDAS [4, 9], epileptic syndrome [5] and signs of pyramidal tract damage.

 

Conclusions. Infliximab leads to significant improvements in hyperactivity and hyperexcitability, as well as stereotypic behavior in children with autism spectrum disorders associated with genetic deficiency of the folate cycle. Responders to immunotherapy are 76 % of patients with this pathology, which is twice as high as with standard therapy. However, there is no effect of infliximab on such manifestations of autism as the level of eye contact and language development. Psychotropic effects of infliximab immunotherapy are closely related to the normalization of previously elevated serum TNF-alpha concentrations and are probably due to the elimination of the pathological activating effect of this pro-inflammatory cytokine on CNS neurons. In parallel, there is an improvement in other clinical syndromes of genetic deficiency of the folate cycle in children with autism spectrum disorders – intestinal pathology, epileptic syndrome, and PANDAS, in the pathogenesis of which, as is known, TNF-alpha and the systemic and intracerebral inflammation induced by this cytokine are involved. However, under the influence of immunotherapy, there is no change in the dynamics of motor deficit in children with symptoms of pyramidal tract damage. Further clinical studies in this direction with a larger number of participants and randomization are necessary to obtain more convincing data.

Efficacy of combined immunotherapy with Propes and Inflamafertin in selective deficiency of NK and NKT cells in children with autism spectrum disorders associated with genetic deficiency of the folate cycle

 Objectives. The results of previous small clinical trials indicate the potential benefit of combination immunotherapy with Propes and Inflamafertin to compensate for NK and NKT cell deficiency due to genetic deficiency of the folate cycle in children with autism spectrum disorders. The purpose of the research was to study the effectiveness of combined immunotherapy with Propes and Inflamafertin in NK and NKT cell deficiency in children with autism spectrum disorders associated with genetic deficiency of the folate cycle. Material and methods. This single-center, prospective, controlled, nonrandomized clinical trial included 96 children aged 2 to 10 years with autism spectrum disorders associated with a genetic folate deficiency (study group, SG). Children of SG received Propes at a dose of 2 ml IM every other day for 3 consecutive months (45 injections), and Inflamafertin at a dose of 2 ml IM every other day for 3 months in a row, alternating with Propes (45 injections). The control group (CG) consisted of 32 children of similar age and gender distribution who suffered from autism spectrum disorders associated with genetic deficiency of the folate cycle, but who did not receive immunotherapy. Outcomes. The number of NK cells reached the lower limit of normal in 39 out of 53 patients (74% of cases), with the resulting deficiency of these lymphocytes, and the average number of NK cells in the blood in SG almost doubling during the 3-month course of immunotherapy (р ˂ 0.05; Z ˂ Z0.05). However, it returned to almost initial level in the 2 months following the discontinuation of immunotherapeutic agents (р˃0.05; Z˃Z0.05). The number of NKT cells was normalized in 78 out of 87 patients (89% of cases) with an initial deficiency of these cells, and the average number of NKT cells in the blood in the DG increased during the course of immunotherapy by half (р ˂ 0.05; Z ˂ Z0.05) and continued to grow for the next 2 months after the discontinuation of immunotropic drugs (р ˂ 0.05; Z ˂ Z0.05). There was a link between immunotherapy and normalization of NK - (χ2 = 18.016; OR = 13.929; 95%CI = 3.498-55.468) and NKT-cells (χ2 = 60.65; OR = 46.800; 95%CI = 14.415-151.937) in the blood with a strong association between these processes (criterion φ = 0.504 and 0.715 respectively; С = 0.450 and 0.581 respectively). Conclusions. Combination immunotherapy with Propes and Inflamafertin is an effective strategy for the treatment of immunodeficiency caused by genetic deficiency of the folate cycle in children with autism spectrum disorders.

 

The results obtained in this controlled non-randomized clinical trial indicate that combination immunotherapy with Propes and Inflamafertin is an effective treatment strategy for immunodeficiency caused by genetic folate deficiency in children with autism spectrum disorders. These biological immunotropic drugs are able to normalize the previously reduced number of NK and NKT cells in the blood in this category of patients during a 3-month course of immunotherapy, with a more frequent, stronger and more lasting effect on NKT cells compared to NK lymphocytes.

  

Conclusion

Folinic acid supplementation is an effective therapy for many people with autism. There are many anomalies that appear, for example those people who test positive for the folate transporter antibodies but a lumbar punction then finds normal levels of folate in the brain.  Many people report agitation or aggression when children take calcium folinate at high doses, but this does not seem to get noted in clinical trials. Nonetheless it looks like everyone with autism should at least make a trial.

Note that you should always add a vitamin B12 supplement when giving high dose calcium folinate. This is because more B12 will be required by the biological processes ongoing in the brain and deficiency will cause side effects.

Many people who respond well to calcium folinate end up needing some kind of immunotherapy on top. IVIG is extremely expensive and quite a bother if you need to take it forever. Some of the therapies from the two papers today also involve a very large number of injections, so are not really practical.  The less intrusive immunotherapies look more practical but are not cheap.

I think that rTMS and tDCS will be attractive to those seeking non-pharmaceutical options that have a scientific basis. The same applies to low level laser therapy, also known as photobiomodulation therapy.

A hidden disability? - Automatic identification of autistic children based on appearance reaches 94% accuracy. Spectrum Needs assessed in a small trial. Bullying in ASD. TCF20 and GABAa receptors. Special educational needs – not so special any more.

 

Today’s post is a summary of a small part of the recent autism research. I am constantly amazed how much autism related research is churned out every day. To anyone who says more autism research is needed, just take a look at how much there already is !!  

 

Facial recognition of Autism?

Those working every day with special needs children have long known that you can pretty quickly spot a child with autism, without any lengthy diagnostic procedure.

Some advocates like to see autism as a hidden disability and believe you cannot “look autistic.” They had better not read this post.

I did write about facial recognition of single gene autisms and rare diseases where a commercialized product (Face2Gene) can now identify 200 conditions with 91% accuracy. This is from a single photo of the face. 

Now Chinese researchers have produce software that can predict autism in pre-schoolers with 94% accuracy based on automated analysis of a video.

Risk assessment and automatic identification of autistic children based on appearance

The diagnosis of Autism Spectrum Disorder (ASD) is mainly based on some diagnostic scales and evaluations by professional doctors, which may have limitations such as subjectivity, time, and cost. This research introduces a novel assessment and auto-identification approach for autistic children based on the appearance of children, which is a relatively objective, fast, and cost-effective approach. Initially, a custom social interaction scenario was developed, followed by a facial data set (ACFD) that contained 187 children, including 92 ASD and 95 children typically developing (TD). Using computer vision techniques, some appearance features of children including facial appearing time, eye concentration analysis, response time to name calls, and emotional expression ability were extracted. Subsequently, these features were combined and machine learning methods were used for the classification of children. Notably, the Bayes classifier achieved a remarkable accuracy of 94.1%. The experimental results show that the extracted visual appearance features can reflect the typical symptoms of children, and the automatic recognition method can provide an auxiliary diagnosis or data support for doctors.

The ASD group were all pre-school children, aged between 20 and 60 months, with an average age of 33.4 months for males and 31.5 months for females.

Like it or not, it seems that autistic toddlers do look different and so it is not a hidden disability. Nobody should be waiting years for a diagnosis.

Bullying

Most autism diagnosed today is mild, level 1 autism. Some of this group really do struggle and can genuinely benefit from pharmacologic therapies.

Bullying is one very common issue that is faced and does not need drug therapy, it needs a different kind of intervention.

A preliminary analysis of teaching children with autism spectrum disorder self-protection skills for bullying situations

Children diagnosed with autism spectrum disorder are at high risk of being bullied, but research on teaching children with autism self-protection skills for bullying situations is scant. We taught five children self-protection skills for two types of bullying (threats and unkind remarks) and consecutive bullying occurrences. We first evaluated behavioral skills training and a textual prompt to teach children to report threats of physical or material harm, provide a disapproving statement after a first unkind remark, and occupy themselves with an activity away from a bully after a second unkind remark. Additional tactics were necessary to aid in the discrimination of bullying situations for two children. There were increases in the self-protection skills with all children. Results further support that an active-learning approach is efficacious in teaching responses to bullying in simulated situations. Considerations for teaching these skills while maintaining trust and rapport with children and caregivers are discussed.

Having a sibling in the same school can be an effective defence against bullying. It might be an older brother, as was the case for Monty, but a younger sister can also be very effective. One episode, of many, I witnessed at school was a young Swedish girl intervening on behalf of her older Aspie-like brother. It really shocked the older boys and certainty impressed me.

I think most bullying affects those with level 1 autism. Those with severe autism would tend to have a 1:1 assistant and if he/she is doing their job there should not be the possibility bullying. I am told that out in the real world kids with level 3 autism do get bullied, which means the system has failed.

From the school’s perspective there is also the opposite issue of the pupil with autism/ADHD attacking other pupils or staff. This does happen and if the child is a large fully-grown male can lead to very serious injury. It is not just those with level 3 autism who can do this.

I think the best strategy to protect against bullying is to ensure your child is in a caring environment at school and is well integrated. This may be easier said than done, but it is possible for many people. Then the other pupils will look out for the one with special needs. This assumes you do not overdo it with who gets to be "special".

Special needs are not so special any more, as was highlighted recently in the UK. For the most privileged group of pupils, those going to private fee-paying schools, 41% are getting special treatment in their exams due to their various special needs. Even in the regular state schools, which for sure have a higher percentage of kids with actual special needs, 26% of pupils get extra time in exams.

Nearly one in three pupils in England given extra time in exams, says regulator

Nearly a third of pupils in England were given 25% extra time to complete their GCSEs and A-level exams following a surge in special exam access arrangements being granted, data from Ofqual has shown.

The figure is higher again among exam candidates in private schools where more than two in five received 25% extra time in the last academic year, according to England’s exams regulator.

The total number of approved special access arrangements for GCSE, AS and A-level exams rose by 12.3% in the 2023/24 school year compared to the year before, the data has revealed.

·         Independent centres 41.8%

·         Sixth form and FE colleges 35%

·         Non-selective state schools 26.5%

It comes as education leaders have suggested more pupils are seeking support after the pandemic due to a rise in young people with special educational needs and disabilities (Send) and mental health issues.

Requests for 25% extra time in exams was the most common approved access arrangement for pupils with learning difficulties or disabilities, followed by computer readers, scribes and speech recognition.

 

Folate supplementation in mothers prevent pesticides causing neurodevelopmental disorders in offspring

There is a lot of research about folate (vitamin B9), birth defects and autism. From the early 1990s women were encouraged to take folate supplements during pregnancy to avoid neural tube defects and other congenital abnormalities.

Some individuals have mutations in the MTHFR gene that impair their ability to convert folic acid into its active form, L-methylfolate. For such individuals, taking methylated folate supplements will be necessary.

More recently we have learned that some people with adequate folate intake can lack folate inside their brain. They have antibodies that block the transmission of folate across the blood brain barrier.

We saw how one clinician is prescribing high dose calcium folinate to couples wishing to reduce the risk of autism in their future offspring, if they test positive themselves for folate receptor auto-antibodies.

As we already know exposure to pesticides and some other unnatural chemicals during pregnancy can lead to neurodevelopmental disorders (NDDs) that include autism.

The paper below is interesting because it looks as how to minimize the potential damage caused by exposure to pyrethroid pesticides, one of the most common classes of pesticides in the US.

Folate prevents the autism-related phenotype caused by developmental pyrethroid exposure in prairie voles 

Neurodevelopmental disorders (NDDs) have dramatically increased in prevalence to an alarming one in six children, and yet both causes and preventions remain elusive. Recent human epidemiology and animal studies have implicated developmental exposure to pyrethroid pesticides, one of the most common classes of pesticides in the US, as an environmental risk factor for autism and NDDs. Our previous research has shown that low-dose chronic developmental pyrethroid exposure (DPE) changes folate metabolites in the adult mouse brain. We hypothesize that DPE acts directly on molecular targets in the folate metabolism pathway, and that high-dose maternal folate supplementation can prevent or reduce the biobehavioral effects of DPE. We exposed pregnant prairie vole dams to vehicle or deltamethrin (3 mg/kg every 3 days) with or without folate supplementation (5 mg/kg methylfolate every 3 days). The resulting DPE offspring showed broad deficits in five behavioral domains relevant to NDDs; increased plasma folate concentrations; and increased neural expression of SHMT1, a cellular folate cycle enzyme. Maternal folate supplementation prevented most of the behavioral phenotype (except for repetitive behaviors) and caused potentially compensatory changes in neural expression of FOLR1 and MTHFR, two other folate-related proteins. We conclude that DPE causes NDD-relevant behavioral deficits; DPE directly alters aspects of folate metabolism; and preventative interventions targeting folate metabolism are effective in reducing, but not eliminating, the behavioral effects of DPE.

 

A round-up of therapies to treat mouse autism

Treating human autism is not yet mainstream, but treating autism in mice has been going on for decades. Of course the idea is to use mouse models with a view to later treating humans.

The paper below is about mice, but it is actually a very good summary of the current status of treatment options more broadly.

It even covers the use of HDAC inhibitors to use epigenetics as a treatment tool. Click on the link to read the full text for free. 

The Use of Nutraceutical and Pharmacological Strategies in Murine Models of Autism Spectrum Disorder 

Autism spectrum disorder (ASD) is a common neurodevelopmental condition mainly characterized by both a scarce aptitude for social interactions or communication and engagement in repetitive behaviors. These primary symptoms can manifest with variable severity and are often paired with a heterogeneous plethora of secondary complications, among which include anxiety, ADHD (attention deficit hyperactivity disorder), cognitive impairment, sleep disorders, sensory alterations, and gastrointestinal issues. So far, no treatment for the core symptoms of ASD has yielded satisfactory results in a clinical setting. Consequently, medical and psychological support for ASD patients has focused on improving quality of life and treating secondary complications. Despite no single cause being identified for the onset and development of ASD, many genetic mutations and risk factors, such as maternal age, fetal exposure to certain drugs, or infections have been linked to the disorder. In preclinical contexts, these correlations have acted as a valuable basis for the development of various murine models that have successfully mimicked ASD-like symptoms and complications. This review aims to summarize the findings of the extensive literature regarding the pharmacological and nutraceutical interventions that have been tested in the main animal models for ASD, and their effects on core symptoms and the anatomical, physiological, or molecular markers of the disorder.

The body of research here summarized suggests that many therapeutic strategies have yielded positive results for ASD core symptoms and ASD-linked cellular, anatomical, and metabolic alterations at the preclinical level. These results ultimately confirm clinical and in vitro evidence regarding the main pathways involved in ASD pathogenesis and hint at the potential for the combination of different types of treatment. The studies reviewed here showed that a treatment’s success or failure in these models usually depends on administration timing. The best results are commonly achieved when protective treatment is given in the first weeks after birth or prenatally. Unfortunately, this is not easily translatable into clinical practice as ASD diagnosis, at the moment, postdates this time window. Moreover, it is notable that most of the treatments employed in these studies did not achieve significant improvements in all the behavioral tests or definitive success in clinical trials. Despite the exact causes for the disparity between promising preclinical results and modest or negative clinical outcomes remaining unknown, a few hypotheses can be formulated. The results of many tests commonly employed to measure sociability and repetitive behaviors in mice can be altered by other symptoms known to be observed in these murine models, such as altered motor coordination, cognitive impairment, and anxiety, which may lead scientists to overestimate the effect of certain treatments on social behavior. Moreover, poor translatability may also be ascribed to the heterogeneity in symptoms and genetic backgrounds found in ASD human patients which, conversely, is far more limited in these mice strains. Ultimately, other possible confounding factors such as interactions with concurrent medications, socio-economic elements, patient lifestyle, or concomitant diseases are significantly more frequent and variable in the human population. Poor translatability may be potentially alleviated by precision medicine approaches in clinical practice and by preclinical testing of single treatments in a variety of ASD murine models. Ultimately, the present literature shows that, despite the limited clinical translational success, murine models can be a valuable tool for testing a variety of treatments in ASD research.

 

Figure 2. Schematic representation of key elements of the mTOR pathway and of therapeutic interventions considered in murine models for ASD. Abbreviations: PIP2: phosphatidylinositol 4,5-bisphosphate PIP3: phosphatidylinositol 3,4,5-bisphosphate PI3K: phosphatidylinositol 3-kinase; PTEN: phosphatase and tensin homolog; Akt: protein kinase B; TSC1: tuberous sclerosis 1; TSC2: tuberous sclerosis 2; AMPK: AMP-activated protein kinase; mTOR: mammalian target of rapamycin; mTORC1: mTOR complex 1; mTORC2: mTOR complex 2; S6K: Ribosomal protein S6 kinase beta-1; eIF4E: eukaryotic Initiation Factor 4E; ULK complex: Unc-51-like kinase 1 complex; PKCa: protein kinase C alpha; P: phosphate group

You can see all the amino acids that have been trialed to modify mTOR (taurine, lysine, histidine and threonine) plus metformin and the potent rapamycin.

Also mentioned is the WHEN in what I call the what, when and where in autism treatment. This is the idea of treatment windows, when a specific therapy can potentially be beneficial.

This very concept was discussed in a recent paper on Rett syndrome.

Protein Loss Triggers Molecular Changes Linked to Rett Syndrome 

Key Facts

·         Early Gene Changes: Loss of MeCP2 leads to immediate gene expression dysregulation, affecting hundreds of genes.

·         Neuronal Impact: Dysregulated genes are linked to neuronal function, causing downstream circuit-level deficits.

·         Therapeutic Window: The study reveals a time frame between molecular changes and neurological symptoms, enabling early intervention opportunities.

Another transcription factor (TCF) that causes autism

There is a lot in this blog about TCF4 (transcription factor 4). Loss of this gene leads to Pitt Hopkins syndrome. Disruption of the gene is associated with schizophrenia and intellectual disability.

Mutations in TCF20 lead to a kind of autism plus intellectual disability called TCF20-Related Neurodevelopmental Disorder. Like Pitt Hopkins, this is a rare disorder, but milder misexpression of the gene is likely much more common. In the recent paper below we see which are the downstream effector genes.

Our old friends the sub-units of GABAa receptors are there. In this case it is GABRA1 and GABRA5 that are reduced.

Both GABRA1 and GABRA5 play essential but distinct roles in regulating neuronal inhibition. GABRA1 primarily contributes to synaptic inhibition and is critical in seizure and anxiety regulation, while GABRA5 is involved in tonic inhibition and cognitive processes.

Malfunctions in GABRA1 and GABRA5 can lead to autism, anxiety, schizophrenia, intellectual disability, epilepsy etc

Regulation of Dendrite and Dendritic Spine Formation by TCF20

Mutations in the Transcription Factor 20 (TCF20) have been identified in patients with autism spectrum disorders (ASDs), intellectual disabilities (IDs), and other neurological issues. Recently, a new syndrome called TCF20-associated neurodevelopmental disorders (TAND) has been described, with specific clinical features. While TCF20's role in the neurogenesis of mouse embryos has been reported, little is known about its molecular function in neurons. In this study, we demonstrate that TCF20 is expressed in all analyzed brain regions in mice, and its expression increases during brain development but decreases in muscle tissue. Our findings suggest that TCF20 plays a central role in dendritic arborization and dendritic spine formation processes. RNA sequencing analysis revealed a downregulation of pre- and postsynaptic pathways in TCF20 knockdown neurons. We also found decreased levels of GABRA1, BDNF, PSD-95, and c-Fos in total homogenates and in synaptosomal preparations of knockdown TCF20 rat cortical cultures. Furthermore, synaptosomal preparations of knockdown TCF20 rat cortical cultures showed significant downregulation of GluN2B and GABRA5, while GluA2 was significantly upregulated. Overall, our data suggest that TCF20 plays an essential role in neuronal development and function by modulating the expression of proteins involved in dendrite and synapse formation and function.

Based on these results, we analyzed the expression of neuronal proteins in TCF20-deficient neurons and found decreased levels of GABRA1, BDNF, PSD-95, and c-Fos in total homogenates (Figure 5) and in synaptosomal preparations (Figure 5) of shTCF20 rat cortical cultures. Additionally, GluN2B and GABRA5 were significantly downregulated, and GluA2 was significantly upregulated in synaptosomal preparations of shTCF20 rat cortical cultures (Figure 5).

On the subject of GABA type A receptor, we have a very recent paper from Poland that delves into this subject in great detail. 

Molecular mechanisms of the GABA type A receptor function

The GABA type A receptor (GABA_AR) belongs to the family of pentameric ligand-gated ion channels and plays a key role in inhibition in adult mammalian brains. Dysfunction of this macromolecule may lead to epilepsy, anxiety disorders, autism, depression, and schizophrenia.

And finally …

Dr Frye has published a study that assessed the effect of his friend Dr Boles’ mitochondrial cocktail.

I did meet Dr Boles a while back at a conference in London. He came with his wife and a stock of NeuroNeeds products for sale, including SpectrumNeeds which was the subject of today’s paper. He was telling me all about the great food just across the border in Mexico and how he learnt Spanish.

A Mitochondrial Supplement Improves Function and Mitochondrial Activity in Autism: A double-blind placebo-controlled cross-over trial

Autism spectrum disorder (ASD) is associated with mitochondrial dysfunction but studies demonstrating the efficacy of treatments are scarce. We sought to determine whether a mitochondrial-targeted dietary supplement designed for children with ASD improved mitochondrial function and ASD symptomatology using a double-blind placebo-controlled cross-over design. Sixteen children [Mean Age 9y 4m; 88% male] with non-syndromic ASD and mitochondrial enzyme abnormalities, as measured by MitoSwab, received weight-adjusted SpectrumNeeds and QNeeds  and placebos matched on taste, texture and appearance during two separate 12-week blocks. Which product received first was randomized. The treatment significantly normalized citrate synthase and complex IV activity as measured by the MitoSwab. Mitochondrial respiration of peripheral blood mononuclear cell respiration, as measured by the Seahorse XFe96  with the mitochondrial oxidative stress test, became more resilient to oxidative stress after the treatment, particularly in children with poor neurodevelopment. The mitochondrial supplement demonstrated significant improvement in standardized parent-rated scales in neurodevelopment, social withdrawal, hyperactivity and caregiver strain with large effect sizes (Cohen’s d’ = 0.77-1.25), while changes measured by the clinical and psychometric instruments were not significantly different. Adverse effects were minimal. This small study on children with ASD and mitochondrial abnormalities demonstrates that a simple, well-tolerated mitochondrial-targeted dietary supplement can improve mitochondrial physiology, ASD symptoms and caregiver wellbeing. Further larger controlled studies need to verify and extend these findings. These findings are significant as children with ASD have few other effective treatments.

Conclusion

Plus ça change, plus c'est la même chose.

The more things change, the more they stay the same.

There isn’t much new that we don’t already know. This is probably good news.

I think for Dr Boles and our Spanish speaking readers you would say "Cuanto más cambian las cosas, más siguen igual." Correct me if I am wrong.

Suramin - Why do Clinical Trials in Autism Struggle to be Convincing? And Oxytocin fails in a large trial.

 

Results from the PaxMedica trial of Suramin

For me, Bumetanide for Autism is now ten-year-old news, for us it has been working since 2012; the next interesting drugs in the pipeline include Suramin and Leucovorin.

It is extremely difficult to trial Suramin at home, or indeed anywhere, and this makes it ever more desirable to many parents.

Leucovorin (calcium folinate) is easy to obtain; you can even buy liquid calcium folinate from iHerb.  You can find out pretty quickly if it produces a profound benefit on your child’s type of autism.

I wish Dr Frye and Professor Ramaekers good luck with the phase 3 trial of Leucovorin.  It certainly works for our adult reader Roger, but not for my 18 year old son, Monty.  Our reader SB’s child recently joined the group of confirmed responders.

After I started writing this post, the results came in of a large (250 children) trial of intranasal oxytocin.  This trial failed to show any benefit, over the placebo, in increasing social behaviors in autistic children. As I have mentioned previously, there is an inherent problem with intranasal oxytocin, the hormone has a very short action, its half-life is 2-6 minutes. It would be much more effective to provide a sustained release of oxytocin, which can indeed be achieved via adding a specific bacterium to the gut. The other problem with intranasal delivery is that you are not supposed to inhale the drug into your lungs, it has to stay in upper part of your nose. How likely is it that parents/children use the spray correctly?  There is even a special dispenser developed for drug delivery to the brain, but did they use it?

In my trials of L. reuteri DSM 17938 it was obvious that the oxytocin improved social behaviors, but I concluded that this was not such a big deal and certainly was not a treatment priority. How would you assess the effect? Very simple, you just count how many times your child is shaking boys’ hands and kissing the girls. I don’t suppose that was the measurement that Duke University used.

Many parents do use Syntocinon nasal spray and this failed trial does not mean they are imagining the effects.  If I was them, I would try L. reuteri DSM 17938 and compare the effect and use whichever is the most beneficial.

  

Suramin 

Suramin is moving towards its Phase 3 clinical trials and, very unusually, two different companies are trying to commercialize the same drug.  One company is PaxMedica and the other is Kuzani, who are ones that cooperate with Dr Naviaux.

In the background is Bayer, the German giant, who have been making Suramin for a hundred years as a therapy for African sleeping sickness and river blindness.  We are told that making Suramin is quite difficult, it is a large molecule; but if they could make it a century ago, how difficult can it really be?  The reality appears to be that Bayer do not want to supply PaxMedica or Kuzani and so they will have to figure out how to make it.  Suramin is sold as a research chemical, but there seem to be questions about its purity. The very cheap Suramin sold on the internet is very likely to be fake.

Today we will look at the data from the South African trial carried out by PaxMedica and take a look at their patent for their intranasal formulation.

We have heard very positive anecdotal reports from the very small initial trials carried out by Professor Naviaux.  Naviaux himself is very interesting, because even though he is not an autism researcher, he is far more knowledgeable than almost all of them on the subject of autism. If you read his papers, they show a rare global understanding of the subject.  This “big picture” is what you need to understand such a heterogenous condition as autism.

In the PaxMedica trial, 44 children completed the trial, so that should be enough to tell us something insightful about whether this drug is effective.

A recurring problem in all autism trials is how well the placebo performs.  Here again in the Paxmedica data we have a very impressive blue line – the placebo.  It is just salt and water and yet it is nearly as good as the trial drug (the orange line).

 

A big part of clinical trials is the statistics used to validate them.

Although I do have a mathematical background, I believe in “seeing is believing”.  The data should be crying out to you what it means.  If it is so nuanced that it needs a statistician to prove the effect, there likely is no effect.

In the above chart we want to see a decreasing slope that would possibly level off as the drug achieved its maximum effect.

What we see are two apparently effective therapies, blue and orange. 

The problem is that blue line is just water, with a bit of salt.

 

Show me the data

What we really want to see are results of each of the 44 participants, not the average.

There are likely groups:

·        Super responders

·        Responders

·        Partial responders

·        Non-responders

 

No statistician is needed.

 

The data from the Suramin trial needs to be presented in the kind of form used in the stem cell trial below:-

Since many hundreds of different biological conditions can lead to an autism diagnosis, we really should not expect there to be any unifying therapy that works for everyone.  Indeed, we should perhaps be suspicious of any therapy claimed to work for everyone.

We always get to hear about the super-responders in anecdotal reports.

We heard great things about Memantine/Namenda, but the phase 3 trial was a failure.  We heard great things about Arbaclofen (R-Baclofen), but the phase 3 trial failed. In Romania our reader Dragos is currently seeing great benefits from the standard version of Baclofen (a mixture of R-Baclofen and S-Baclofen).

My son is a super-responder to Bumetanide, but I know that most people are not. However, when I came across the “bumetanide has stopped” working phenomena, it became clear that the situation is more complex than a single one-time evaluation. We know why bumetanide can “stop working” and how to make it “start working again”.  An increase in inflammatory cytokines from the periphery (i.e. outside the brain) further increases the expression of NKCC1 in the brain and negates the effect of bumetanide; reduce the inflammation and bumetanide will start to work again.

  

Why does the placebo always do well in autism trials?

The assessments used to measure outcome are all observational, they are not blood tests or MRI scans.  They are highly subjective.

It has been suggested that just being in an autism trial improves symptoms of autism.  The parents give more attention to the child and this then skews the results.

My way round this problem in my n=1 trials was always to tell nobody about the new trial I was making and wait for unprompted feedback.  This works really well.

 

 

Who chooses the trial goal (the primary endpoint)?

I like the fact that in the Leucovorin trial the goal is speech.  It is a very simple target and relatively easy to measure.

For Bumetanide, I did suggest to the researchers that they used change in IQ as an endpoint.  Nice and simple, start with kids with IQ<70 and then recruit those who have a negative reaction (paradoxical response) to Valium/diazepam.  Then expect an increase in measured IQ of 10 to 40 points.  Then you would have a successful phase 3 trial.    

In many previous trials that ultimately failed, some people did see a benefit, but they were different benefits.  I did get a reader telling me how great Memantine (Namenda) had been for her child, when I asked why she told me that it was the only therapy that had ever solved her child GI problems.  That certainly was never considered as a trial goal/endpoint.

In my trial of Pioglitazone, I read the research about both the mechanism of action and the observed effects listed in the phase 2 trial:

"improvement was observed in social withdrawal, repetitive behaviors, and externalizing behaviors as measured by the Aberrant Behavior Checklist (ABC), Child Yale-Brown Obsessive Compulsive Scale (CY-BOCS), and Repetitive Behavior Scale–Revised (RBS-R)."

I was targeting something entirely different.  Based on the mechanism of action, specifically the reduction of the inflammatory cytokine IL-6, I expected a reduction in summertime raging.  It worked exactly as hoped for. This is the second summer we have used it.

Our reader Sara’s initial assessment of the effect of Pioglitazone is focused on the improvement in sleeping patterns.  This is great, assuming the benefit is maintained, but it is an entirely different benefit.

 

Was the trial drug actually taken?

I suspect in the bumetanide trial, many parents did not give the trial drug every day, as per their instructions, because the diuresis was too much bother.  I know from reader comments and emails that many parents stop giving bumetanide, even though their child is a responder.  Some schools refuse to allow bumetanide because of the disruption caused by frequent toilet breaks.

Because Suramin is given once a month by infusion, there is 100% certainty that the drug or placebo was actually taken.  This is a big plus.

Was the intranasal oxytocin correctly administered in the recent trial? I doubt it.

The problem with Leucovorin is that in a minority of children is causes aggression, even if you follow Prof Ramaeker’s advice and very slowly increase the dosage.  In the phase 3 trial parents should be informed of this possibility and told to report it and be invited to withdraw from the trial.  If they just stop the therapy to halt the aggression, but their data remains included in the study, the results are invalidated.

 

Intranasal Suramin

Patents are often a good source of information and they do also tell you something about the people who wrote them.

Here below is PaxMedica's patent for intranasal suramin:-

Compositions and methods for treating central nervous system disorders

These results demonstrate that an antipurinergic agent such as suramin can be delivered intranasally to achieve plasma and brain tissue levels and that variations in the brain tissue to plasma partitioning ratio can be observed. These results demonstrate that an antipurinergic agent such as suramin can be delivered to the brain of a mammal by intranasal (IN) administration. 

The following Table 1 provides the averaged accumulated amount, in mg, of suramin that has penetrated as a function of time

But how can the accumulated level after 6 hours be less than after 5 hours?

The results of the study are also shown graphically in FIG. 1 where the cumulative amount (mg) of drug permeated was plotted versus time in hours. These data demonstrate that Formulation B containing methyl β-cyclodextrin (methyl betadex) provides significantly better penetration, versus Formulations, A , C, and D in the tissue permeation assay. Also, as is seen from a comparison of Formulations A and D, having a higher drug concentration can be advantageous to increasing permeation.

 

Formulation A - suramin hexa-sodium salt at 100 mg/mL in water (no excipients) Formulation B - suramin hexa-sodium salt at 100 mg/mL in water, with 40% methyl β-cyclodextrin (methyl betadex) Formulation C - suramin hexa-sodium salt at 100 mg/mL in water, with 40% HP (hydroxyl propyl) -cyclodextrin Formulation D - suramin hexa-sodium salt at 160 mg/mL in water (no excipients)

 

FIG. 7 shows a plot comparing the total percentage of suramin in plasma in mice when administered by intraperitoneal (IP) injection once weekly for 4 weeks (28 days), intranasally (IN) daily for 28 days, intranasally (IN) every other day for 28 days, and intranasally (IN) once per week for 4 weeks (28 days).

 

FIG. 8 shows a plot comparing the total percentage of suramin in brain tissue in mice when administered by intraperitoneal (IP) injection once weekly for 4 weeks (28 days), intranasally (IN) daily for 28 days, intranasally (IN) every other day for 28 days, and intranasally (IN) once per week for 4 weeks (28 days).

 

Does anyone think the above chart makes any sense? 

 

The mice were maintained in group cages (6 mice per cage based on treatment group) in a controlled environment (temperature: 2 1.5 ± 4.5 °C and relative humidity: 35-55%) under a standard 12-hour light/1 2-hour dark lighting cycle (lights on at 06:00). Mice were accommodated to the research facility for approximately a week. Body weights of all mice were recorded for health monitoring purposes.

The mice were divided into the following 5 test groups, with 6 mice per group.

Group 1: Intraperitoneal (IP) injection of suramin, 20 mg/kg, administered weekly to animals beginning at 9 weeks of age and continuing for four weeks (i.e. given at Age Weeks 9 , 10 , 11 and 12). The suramin was formulated in Normal saline solution.

Group 2 : Intraperitoneal (IP) injection of saline, 5 mL/g, administered weekly to animals beginning at 9 weeks of age and continuing for four weeks (i.e. given at Age Weeks 9 , 10 , 11 and 12). This was a control group.

Group 3 : Intranasal (IN) administration of a formulation, described below, of suramin, at a concentration of 100 mg/mL x 6 mL per spray, administered as one spray per nostril, one time per day, (interval of each application is around 2 minutes to ensure absorption) for 28 days (total of 56 sprays over 28 day period) beginning at 9 weeks of age (i.e. given daily during Age Weeks 9 , 10 , 11 and 12).

Group 4 : Intranasal (IN) administration of a formulation, described below, of suramin, at a concentration of 100 mg/mL x 6 mL per spray, administered as one spray per nostril, one time every other day, for 28 days (total of 28 sprays over 28 day period) beginning at 9 weeks of age (i.e. given once every other day during Age Weeks 9 , 10, 11 and 12).

Group 5 : Intranasal (IN) administration of a formulation, described below, of suramin, at a concentration of 100 mg/mL x 6 ml_ per spray, administered as one spray per nostril, one time every week, for 4 weeks (28 days) (total of 8 sprays over 28 day period) beginning at 9 weeks of age (i.e. given once weekly during Age Weeks 9 , 10 , 11 and 12).

 

This question was posed to me:-

A nasal spray in a human is about 0.1 ml, how do you give a tiny mouse 6 ml per nostril?  Even 0.6 ml looks implausible.

 

Conclusion

Will Suramin pass a phase 3 trial?  I think if it is trialed on a random group of 400 young people with moderate or severe autism, it will very likely fail.

Professor Naviaux believes Suramin may be a unifying therapy, one that works in all autism.  The results from the PaxMedica study do not support this.

PaxMedica has the data showing the individual results.  Are there super-responders? Are there non-responders? Does Suramin perhaps make some people's autism worse?  All we can see is the average response, which is marginally better than the placebo; not what we expected after seeing the initial study.

Expecting Suramin to work well for everyone is raising the bar too high.  Try and identify markers for the responders and super-responders and then limit the phase 3 trial to these people.

Is intranasal delivery of Suramin going to achieve a therapeutic level inside the human brain?  Hopefully yes, but it may not work.

Is long term use of Suramin going to be safe? Will it require ever-increasing doses? Nobody knows, and note that safety was the original concern when Suramin’s use was proposed by Naviaux.

Intranasal administration has the best chance of being totally safe.  Spend a little extra money on the clever dispenser covered in this old post, that keeps 100% of the drug in the right place.

 

https://epiphanyasd.blogspot.com/2015/09/opn-300-oxytocin-and-autism.html

 

Maybe get someone other than a lawyer, to proof read your patent.