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Thursday 4 April 2024

Advances in personalized medicine to treat Autism/IDD – Rett syndrome as an example. Also, Piperine to upregulate KCC2, but what about its direct effect on GABAa receptors?

 

Source:  https://www.cell.com/neuron/pdf/S0896-6273(21)00466-9.pdf


Today’s post is drawn from a workshop I am invited to present at an autism conference in Abu Dhabi.

I decided to talk about advances in personalized medicine – no surprise there.  Since I have 2 ½ hours, I thought I will need some interesting examples to maintain the audiences interest.  One such topic is going to be Rett syndrome.

I regard Rett syndrome and all the other such syndromes in this blog as “single gene autisms” (monogenic autism).  If you apply the American DSM classification, from 2013 onwards Rett syndrome is no longer part of autism.  Hopefully there are no such purists attending in Abu Dhabi. 

Two gene therapies for Rett syndrome are currently undergoing human trials and one drug therapy has been FDA approved.  This looks very encouraging, so let’s dig a little deeper.



Rett syndrome can present with a wide range of disability ranging from mild to severe. 

Rett syndrome is the second most common cause of severe intellectual disability after Down syndrome.

Other symptoms may include:

      Loss of speech

      Loss of purposeful use of hands

      Loss of mobility or gait disturbances

      Loss of muscle tone

      Seizures or Rett “episodes”

      Scoliosis

      Breathing issues

      Sleep disturbances

      Slowed rate of growth for head, feet and hands

Here are the new therapies: 


TSHA-102: This gene therapy, developed by Taysha Therapeutics, is a gene replacement therapy that aims to deliver a functional copy of the MECP2 gene to brain cells.  It utilizes an AAV-9 virus to carry the miniMECP2 gene product into cells for the body to produce more MeCP2 protein, which is deficient in Rett syndrome. As of February 2024, Taysha completed dosing for the first cohort (low dose) in their REVEAL Phase 1/2 adolescent and adult trial in Canada, with positive interim data on safety. They are also conducting trials in the US for both pediatric and adolescent/adult populations.

NGN-401: This gene therapy, by Neurogene Inc., employs a different approach. It uses an AAV9 vector to deliver a regulated version of the MECP2 gene called EXACT. This technology aims to control the amount of MECP2 protein produced by the gene, mitigating the risk of overproduction. NGN-401 is currently in a Phase 1/2 trial for girls with Rett syndrome aged 4 to 10 years old.


Daybue (trofinetide)

Daybue is the first and only FDA-approved treatment specifically for Rett syndrome in adults and children two years of age and older. It is not a gene therapy, but rather a medication taken orally.

The optimistic AI generated view:

Here's a breakdown of Daybue for Rett syndrome:

  • Mechanism: The exact way Daybue works in Rett syndrome isn't fully understood, but it's believed to target neuroinflammation and support synaptic function.
  • Dosage: The recommended dose is based on the patient's weight and is taken twice daily, morning and evening, with or without food.
  • Administration: Daybue comes as an oral solution and can be taken directly or through a gastrostomy tube if swallowing is difficult.
  • Efficacy: Studies have shown that Daybue can improve symptoms of Rett syndrome, including reducing scores on the Rett Syndrome Behavior Questionnaire (RSBQ) and showing improvement on the Clinical Global Impression-Improvement (CGI-I) scale.
  • Side Effects: The most common side effects of Daybue are diarrhea and vomiting. Weight loss can also occur in some patients. It's important to consult with a healthcare professional for monitoring and managing any potential side effects.

Daybue is an expensive medication. Here's what we know about the cost:

  • List Price: The list price of Daybue is around $21.10 per milliliter.
  • Annual Cost: This translates to an estimated average annual cost of around $375,000 for patients.
  • Dosage Variability: It's important to note that the dosage of Daybue is based on a patient's weight, so the annual cost can vary depending on the individual.

Insurance and Assistance Programs:

  • The high cost of Daybue highlights the importance of insurance coverage. Whether insurance covers Daybue and to what extent will depend on your specific plan.
  • The manufacturer, Acadia Pharmaceuticals, offers a copay program called Daybue Acadia Connect. This program may help eligible commercially insured patients pay $0 for their monthly prescription.

What are the parents' groups saying? 

Not as good as you might be expecting for $375,000 a year.




Affordable potential alternatives to Daybue/Trofinetide

Daybue/Trofinetide is the product of decades of research into a growth factor called IGF-1.

It is a complicated subject and as usual the abbreviations can be confusing.

As you will see below there already is an OTC product commercialized by one of the original researchers, Dr Jian Guan.

One Rett syndrome parent, who reads this blog, has trialed cGP and sees a benefit. You rather wonder why the Phelan-McDermid, Pitt Hopkins, Angelman and Prader-Willi parents don’t follow him and splash out 50 USD and make a trial.


 


 



Gene-therapy

Gene therapy is undoubtedly very clever and ultimately will likely be the best therapy.  It still may not be that silver bullet.

To be effective gene therapy needs to be given at a very young age, ideally as a fetal therapy prior to birth. Note that we saw that in the Rett mouse model they gave bumetanide to the pregnant mother just before birth.

Fetal therapy is not a crazy idea and much is already written about it; many pregnancies are terminated because genetic anomalies are detected prior to birth. Down syndrome is the best-known example. Fetal therapy is realistic for some disorders.

Girls with Rett syndrome are often diagnosed first with idiopathic autism and then years later with a more precise diagnosis of Rett syndrome. This is a common experience among readers of this blog.


Classic Rett syndrome 

The average age of diagnosis for this form is around 2.5 years old in the US and 5 years old in the UK.  Why do you think that is?

Research in mouse models has shown that the effect of gene therapy ranges from curative when given extremely young to more limited the later it is given.


Off-target effects

Gene therapy has the potential for off-target effects. This is a significant concern in the field and researchers are actively working on ways to minimize these risks. Here is a breakdown of what off-target effects are and why they matter:

During gene therapy, a modified gene is delivered to target cells with the aim of correcting a genetic defect.

Ideally, the modified gene integrates into the intended location in the genome.

However, there's a chance it might insert itself into unintended locations (off-target sites).


Potential Consequences of Off-Target Effects

Disrupting normal genes at off-target sites could lead to unpredictable and potentially harmful consequences. This could include triggering uncontrolled cell growth, which is a risk factor for cancer.

It can also cause unexpected side effects depending on which genes are accidentally disrupted.


Minimizing Off-Target Effects

Researchers are developing various strategies to improve the accuracy and specificity of gene therapy techniques.

This includes using more precise gene editing tools like CRISPR-Cas9 with optimized guide RNAs to reduce off-target edits.

Additionally, researchers are working on methods to detect and potentially repair any off-target modifications that might occur.


Over-expression of the target gene

Yes, there is a possibility that the replaced gene in gene therapy could overproduce the expressed protein. This can be a potential complication and researchers are working on ways to control the level of protein expression. Here's a breakdown of the concern:

  • Gene Dosing: Ideally, gene therapy aims to deliver a functional copy of the gene at the right amount to compensate for the deficiency.
  • Overproduction Risks: However, if the delivered gene is too active or multiple copies are inserted, it can lead to overproduction of the protein.

Consequences of Protein Overproduction:

  • Overproduction of a protein can disrupt the delicate balance in the cell, potentially leading to cell dysfunction or even cell death.
  • In some cases, the protein itself might have harmful effects if present in excessive amounts.


Controlling Protein Expression:

Researchers are developing several strategies to control protein expression in gene therapy:
    • Promoter selection: Using promoters that have a weaker switch can help regulate protein production.
    • Viral vectors: Engineering viral vectors to control the number of gene copies delivered to cells.
    • Inducible systems: Developing gene therapy methods where the expression of the introduced gene can be turned on and off as needed.


The cost of gene therapy

      Despite the high cost, gene therapy can be a cost-effective treatment for some diseases. This is because it can eliminate the need for lifelong treatment with other medications.

      Here are some examples of the cost of currently available pediatric gene therapies:

      Luxturna (gene therapy for Leber congenital amaurosis type 10): $425,000

      Zolgensma (gene therapy for spinal muscular atrophy type 1): $2.1 million

      Skysona (gene therapy for adrenoleukodystrophy): $3 million


Piperine to correct KCC2 expression in Rett syndrome?

One key feature of Rett syndrome is impaired cognition.

As regular readers are aware, there are many types of treatable intellectual disability (ID).

One type of treatable ID is caused when the GABA developmental switch fails to occur shortly after birth.  This creates an excitatory/inhibitory imbalance in neurons which impairs cognition and lowers IQ.

The faulty GABA switch is a feature of many types of autism, but far from all of them.

By using pharmaceuticals to lower chloride within neurons, you can compensate for the failure of the GABA switch.

This treatment can be achieved by:

1.     Blocking or down regulating NKCC1

2.     Up regulating KCC2

In the paper below they look at up regulating KCC2

Pharmacological enhancement of KCC2 gene expression exerts therapeutic effects on human Rett syndrome neurons and Mecp2 mutant mice

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl CpG binding protein 2 (MECP2) gene. There are currently no approved treatments for RTT. The expression of K+/Cl cotransporter 2 (KCC2), a neuron-specific protein, has been found to be reduced in human RTT neurons and in RTT mouse models, suggesting that KCC2 might play a role in the pathophysiology of RTT.

Injection of KEEC KW-2449 or piperine in Mecp2 mutant mice ameliorated disease-associated respiratory and locomotion phenotypes. The small-molecule compounds described in our study may have therapeutic effects not only in RTT but also in other neurological disorders involving dysregulation of KCC2.

Thus, our data demonstrate that activation of the SIRT1 pathway or the TRPV1 channel enhances KCC2 expression in RTT human neurons.

Treatment with piperine (10 μM), an activator of the TRPV1 channel (51), induced a significant rise in KCC2 expression in cultured human neurons 

We already knew this was likely from earlier research from Ben Ari, see below for a reminder.  Is Piperine an interesting option for those restricted to OTC interventions?

Early alterations in a mouse model of Rett syndrome: the GABA developmental shift is abolished at birth

Genetic mutations of the Methyl-CpG-binding protein-2 (MECP2) gene underlie Rett syndrome (RTT). Developmental processes are often considered to be irrelevant in RTT pathogenesis but neuronal activity at birth has not been recorded. We report that the GABA developmental shift at birth is abolished in CA3 pyramidal neurons of Mecp2-/y mice and the glutamatergic/GABAergic postsynaptic currents (PSCs) ratio is increased. Two weeks later, GABA exerts strong excitatory actions, the glutamatergic/GABAergic PSCs ratio is enhanced, hyper-synchronized activity is present and metabotropic long-term depression (LTD) is impacted. One day before delivery, maternal administration of the NKCC1 chloride importer antagonist bumetanide restored these parameters but not respiratory or weight deficits, nor the onset of mortality. Results suggest that birth is a critical period in RTT with important alterations that can be attenuated by bumetanide raising the possibility of early treatment of the disorder.

One day before delivery, maternal administration of the NKCC1 chloride importer antagonist bumetanide restored these parameters but not respiratory or weight deficits, nor the onset of mortality. Results suggest that birth is a critical period in RTT with important alterations that can be attenuated by bumetanide raising the possibility of early treatment of the disorder.

Treating the mother prior to delivery with bumetanide was a partially effective therapy in the mouse model of Rett syndrome.


Piperine

Bumetanide is cheap and very possibly effective in human Rett syndrome, but it is a prescription drug.

Piperine is an OTC supplement and a compound found in black pepper. By activating the TRPV1 channel it causes an increase in expression of the KCC2 transporter that allows flow of chloride out of neurons. So piperine should lower chloride inside neurons.  Piperine can cross the blood brain barrier, so when taken orally it should have some effect on intracellular chloride.


Piperine is also a positive allosteric modulator of GABAA receptors

This means that piperine multiplies the effect of whatever GABA is around. This means that in typical people piperine should have anti-anxiety effects.

Piperine was recently found to interact with a previously unknown  benzodiazepine-independent binding site.

Researchers are currently toying with the piperine molecule to try and separate the effect on TRPV1 from the effects on  GABAA.  They want to create 2 new drugs.

1.     a selective TRPV1 activator

2.     a selective GABAA modulator (PAM)


Piperine as an alternative or complement to Bumetanide?

One effect of piperine would be great to have (TRPV1 activator) but the second effect would not be helpful (positive allosteric modulator of GABAA).

The question is what is the net effect. Nobody will be able to answer that without a human trial.

I was advised long ago by one drug developer than it is best to focus on reducing flow into neurons via NKCC1, rather than increase its exit by KCC2, because nobody had yet been successful with KCC2; many have tried.  KCC2 plays a key role in neuropathic pain and that is why it has been researched.


Conclusion

We did see years ago that taking coffee with your bumetanide made sense. Coffee contains compounds that are OAT3 inhibitors and slow down the excretion of bumetanide from the body; coffee increases the effect of bumetanide. You can achieve something very similar by just increasing the dose of bumetanide.

Taking black pepper (piperine) with your bumetanide might be good, or might not be. It certainly would be easy to find out. As with Daybue/Trofinetide, the result is likely to vary from person to person. If GABA function, post- bumetanide, is still a bit excitatory amplifying GABA signaling will make autism worse. If GABA function has been shifted to inhibitory then amplifying GABA signaling will be calming.

Gene therapy will require much earlier diagnosis of single gene autisms.

“Precision medicine” therapies like Daybue/Trofinetide may not be that precise after all and large variations exist in the response, even among children with the same affected gene.

The huge expense means that for most of the world they will see no benefit from gene therapy or indeed “precision medicine.”

The low hanging fruit is to repurpose affordable existing drugs and get the benefit from their secondary effects.  This is what I term personalized medicine.

The research clearly indicates that some girls with Rett syndrome likely will benefit from Bumetanide therapy. For a young child this therapy would cost 50 US dollars/euros a year, if you pay the actual price for generics.

Why are they trialing genetic therapies for Rett instead of first doing the obvious thing and trialing cheap bumetanide? They will likely be able to sell the gene therapy for $2 million a shot.  There is little interest in trialing a $50 a year therapy.

Our new reader from Turkey, MÜCADELECI ANNE DENIZ ( = FIGHTING MOTHER DENIZ), likely does not have $2 million to spend, but seems to be on the way to creating her own personalized medicine therapy for her son. Good luck to her.

As to the cGP Max supplement, it seems to work for some and have no effect in others. Nobody has reported any side effects. It looks worth a try for Rett syndrome.  As a supplement it is not cheap, that is until you see what they charge for Daybue. 








43 comments:

  1. Having a pre-birth diagnosis will in some cases lead to early treatment, but it is important to realize that in other cases it will instead lead to an abortion. Thus it is likely that gene therapies will be aimed mainly at already born individuals, at least in the nearest future.
    Of course, gene therapy might not be a silver bullet that resolves just every symptom, but in many disorders it will probably have a life-changing (or -saving) effect on the impacted individual. I rather see gene therapy as the long-term goal to achieve, whilst repurposing of drugs should be the primary short-term goal.
    /Ling

    ReplyDelete
  2. For the cGP supplement, one can check the https://www.rettsyndrome.eu/news/cgpmax-supplement/ page for a FAQ and dosage. The PDF is available in Spanish too.

    ReplyDelete
  3. Saw this link today, rehashing the idea of r-baclofen. Does anyone know how to access arbaclofen or r-baclofen to try?

    https://medicalxpress.com/news/2024-04-chemical-differently-autistic-eye.html?fbclid=IwAR14OAiaTlLCMhrN0ZQKiZ9L63WwZ-Cgy8X8sbCLQ0WFtYDptxQSZTVEWD0

    ReplyDelete
    Replies
    1. Baclofen is a cheap generic drug, but it is a mixture of r-baclofen and s-baclofen.

      The question is whether the s-baclofen gets in the way of the good effects of r-baclofen. In alcohol dependence this is being researched.

      Some people with autism do respond well to the cheap baclofen. Many do not.

      I tried generic baclofen years ago.

      Some people with autism have tight claw-like hands. They cannot use a keyboard. They really should benefit from the cheap baclofen.

      Delete
  4. Peter, do you know anything about type I Interferonopathies?

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10175883/

    Stephen

    ReplyDelete
    Replies
    1. Yeah, I got the lab results back from Dr. Jyonouchi laboratory. My son Stephen with Profound Autism has an over active immune system with increased IFN-gamma. He lost the brakes to stop his immune system. His blood was compared to his sister's who is neuro typically.

      This is from the my favorite bumetanide study.

      "Our finding of an immuno-behavioural covariation highlights the role of the immune system in the clinical effect of bumetanide in young children with ASD. IFN-γ, as a T helper cell 1 (Th1) cytokine with proinflammatory effects, was selected by the sCCA algorithm to be one of the three cytokines to form the canonical score that was associated with the improvement in CARS. Compared to controls, higher level of IFN-γ has been reported in the brain tissue [22], cerebrospinal fluid (CSF) [23], plasma [35] and peripheral blood mononuclear cell (PBMC) [36] in ASD patients, and lower level has been observed in neonatal dried blood samples (n-DBSS) of ASD children [37]. Accumulating evidences support that IFN-γ can inhibit chloride secretion [38] and down-regulate both the NKCC1 expression [16, 38] and the Na+-K+-ATPase expression [16], which had been implicated in the GABAergic dysfunction in ASD [10, 39]. Indirectly, an animal study also showed that stimulation with high concentration of IFN-γ could increase the expression of IL-1β [40], which is an inflammatory cytokine that can affect the expression of chloride transporters and delay the developmental switch of GABA signalling [17]. Therefore, the immune system may interact with the mechanism of action of bumetanide to restore the GABA function in ASD."

      She suggested cibinqo and colchicine for his inflammatory response.

      Rapamycin, ibuprofen, and bumetanide also work for him so it makes sense.

      -Stephen

      Delete
    2. Stephen, my daughter is also an immune based autism case. Can you give me an iverview of symptoms, diagnostics and therapies so I can see if there is something we did not do?

      Delete
    3. I would first make an appointment with Dr. Jyonouchi. She has her own lab in which she can make the proper diagnosis. She compared my son's blood to his sister. That's how she was able to figure out the difference in immune response. I guess the biggest give away was he was always sick. Like every two weeks he would have a new cold. As for immunotherapy ibuprofen works well for him. Jak1 inhibitor are extremely expensive so I will see how that will work out when I finally get ahold of them. Bumetanide and Rapamycin do work too.

      Delete
    4. I forgot he take daily Leucovorin and xolair monthly. I would highly suggest the xolair.

      Delete
    5. Also, during my Liptor trial he did have positives gains too. I guess statins block ifn-a/ifn-b (T1-ifns).

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320251/

      Delete
  5. Also, please add Cibinqo to your ASD medication list. It's a jak1 inhibitor. It's utilized for over reactive immune system. Bumetanide stops the down stream reaction caused by increased ifn-y but you can use this drug to stop the reaction before it starts.

    Stephen

    ReplyDelete
    Replies
    1. The JAK/STAT signaling pathway modulates several immune pathways. It is very relevant to some types of autism.

      There are four different JAK proteins (JAK1, JAK2, JAK3, and TYK2) and seven distinct STAT proteins (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6)

      In the paper below they used a STAT3 inhibitor

      The Stat3 inhibitor, S3I-201, downregulates lymphocyte activation markers, chemokine receptors, and inflammatory cytokines in the BTBR T+ Itpr3tf/J mouse model of autism

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8648435/

      BTBR mice experienced a significant induction in activation marker expression.

      S3I-201 decreased activation markers and inflammatory cytokines in BTBR mice.

      Treatment with S3I-201 inhibited chemokine receptor expression in BTBR mice.

      S3I-201 improved immune abnormalities in BTBR mice.

      STAT3 inhibitor could be a potential therapeutic option for autism.

      Delete
  6. i bought bumetanid from mexico. now my wife prenancy second kid. my firsd kid autism. so maybe if my wife use bumetanid before born. is it safe ? its very important to me. plz recommend

    ReplyDelete
    Replies
    1. This is totally wrong. Please don’t do this. This is not for pregnant women or small babies.

      Delete
    2. Giving NAC during pregnancy has been trialed and shown to be safe. This was to protect against miscarriage.

      Calcium folinate is being given during pregnancy in Belgium to protect against autism. I was surprised to read that.

      Exposing pregnant women to bacteria from pets has been shown to reduce the incidence of autoimmune disease.

      Avoiding stress during pregnancy reduces the chances of maternal immune activation induced autism.

      Oxytocin at birth is sometimes used to benefit the mother, in autism the benefit goes to the child to initiate the GABA developmental shift.

      Bumetanide before birth works for mice with Rett syndrome. Bumetanide from 6 months of age has been trialed for febrile seizures. It was safe, but did not help.

      Delete
    3. Give 81mg aspirin daily. It will decrease il-6 and inflammation. It's used for millions of pregnant women for IUGR and its extremely safe.

      -Stephen

      Delete
    4. No need to post. This is my meeting with Jyonouchi. At the 20 min mark we talk about immune activation.

      https://youtu.be/RwUp1-X0z10

      Anastasia has the ability to control her immune system Stephen does not.

      -Stephen

      Delete
    5. I had low Paap-A harmone during my pregnancy and was on Aspirin from 14 weeks onwards upto 32 weeks . May be this has helped. My son has mild autism.

      Delete
  7. Peter, plz send me a link about nac safe to prenancy

    ReplyDelete
    Replies
    1. This is the paper I was referring to

      https://www.sciencedirect.com/science/article/abs/pii/S1472648310603227

      But there are others, like this one

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451831/

      So it is clear that NAC is viewed as safe during pregnancy.

      Delete
    2. so you think bumetanid dont safe or don work for prenancy ?

      Delete
    3. Prior to birth GABA should function as excitatory in the brain.

      At birth a change should be triggered so that within about 14 days after birth chloride levels in neurons are falling which shifts GABA to act as an inhibitory neurotransmitter.

      You would not want GABA to be inhibitory during the pregnancy, just from birth.

      Even if it was proved to be 100% safe, giving bumetanide throughout pregnancy would not be wise.

      The key is to trigger the GABA developmental switch. One way would appear to be oxytocin at birth.

      It is a surprise that bumetanide had a good and long-lasting effect in a mouse model of Rett syndrome when given at the last stage of pregnancy. In children and adults with autism you have to keep taking bumetanide every day, because the GABA developmental switch never occurred.

      There are very many different types of autism.

      Delete
  8. Stephen, plz send me a link about asprrin

    ReplyDelete
  9. https://www.sciencedirect.com/science/article/abs/pii/S0301211517300039

    ReplyDelete
  10. Peter, do you know anyone taking Dupixent?

    -Stephen

    ReplyDelete
    Replies
    1. Stephen, I do not, but it looks like it may improve symptoms of other issues in autism/ADHD. This is what you would expect.

      Dupilumab treatment for atopic dermatitis is associated with decreased utilization of psychostimulants for attention deficit hyperactivity disorder: A retrospective cohort study

      Delete
    2. I just it find it interesting. It maybe can reset b cells.

      https://pubmed.ncbi.nlm.nih.gov/36189576/

      Delete
    3. Hi Peter, here is an interesting rabbit hole. Probably why gluten free and dairy free diets are useful in ASD kids.

      The result of the single-arm meta-analysis showed an overall prevalence of ASD in the population with EGID of 21.59% (95% CI: 10.73-38.67). There was an association between EGID and ASD (OR: 3.44; 95% CI: 1.25-2.21), also significant when restricted only to EoE (OR: 3.70; 95% CI: 2.71-5.70).

      Autism in patients with eosinophilic gastrointestinal disease: A systematic review with meta-analysis

      https://pubmed.ncbi.nlm.nih.gov/38581140/#:~:text=The%20result%20of%20the%20single,CI%3A%202.71%2D5.70).

      -Stephen

      Delete
    4. Dupilumab Leads to Clinical Improvements including the Acquisition of Tolerance to Causative Foods in Non-Eosinophilic Esophagitis Eosinophilic Gastrointestinal Disorders

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9856177/

      Delete
  11. I recently came across a paper that linked hyperacusis(intolerance to sound) to microglia activation. I am wondering if that could be the reason for sound intolerance we see in autism. There was an unrelated case study of two boys(neurotypical) having success with ginkgo biloba for hyperacusis, and it is well known that ginkgo biloba has anti-inflammatory properties. What are your thoughts on this, Peter ? Did you notice any positive response with your son on clemastine with respect to sound tolerance ?

    ReplyDelete
    Replies
    1. I also saw that paper implicating loss of the ion channel Nav1.2 affecting myelination and thus increasing sound sensitity. I am going to write about it in the next post. It is interesting but not at all simple and so far nobody fully understands it.

      In that paper it said:

      "How are Nav1.2 channels, encoded by Scn2a, involved in OL maturation and myelination? One possible explanation is that the activation of Nav1.2 may be pivotal for triggering Cav channel activation, leading to a Ca2+ flux within OLs, which is involved in OL proliferation, migration, and differentiation. Specifically, Ca2+ signaling facilitated by R-type Cav in myelin sheaths at paranodal regions, might influence the growth of myelin sheaths. To activate high-voltage activated calcium channels such as L- and R-Type efficiently, the activation of Nav1.2 channels should be required for depolarizing OL membrane to around -30 mV . Consequently, the synergic interplay between Nav1.2 and Cav channels could amplify calcium signaling in OLs, initiating the differentiation and maturation processes."

      I saw no benefit from taking clemastine on sound sensitivity. However I see and almost immediate benefit from taking 250mg of Ponstan. Some others have noted the exact same effect, but in others there is no benefit.

      Acute inflammation does make some people's sound sensitivity much worse. So anything broadly anti-inflammatory might help.

      The 2 case histories from Brazil showed that Gingko biloba extract 80mg twice a day for 2 months was effective. This is actually an existing tinnitus therapy.

      Management of hyperacusis in children – two case reports
      http://www.bjorl.org//en-management-hyperacusis-in-children--articulo-S1808869416300209

      Delete
  12. Peter, have you ever stopped giving Monty atorvastatin? If so, was there regression?

    Atorvastatin increases il4 in the brain and attenuates inf-gamma.

    https://pubmed.ncbi.nlm.nih.gov/17981803/

    Stephen

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    Replies
    1. Yes, I have stopped Atorvastatin in the past, and indeed all the other therapies. There is a cognitive loss.

      Delete
    2. Yea, xolair wears off too. It usually tapers off around a month or so. I guess that's why Jyonouchi did bi-monthly shots.

      Delete
    3. Xolair would probably work for alzheimer's...

      New Regulatory Roles of Galectin-3 in High-Affinity IgE Receptor Signaling

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836217/

      Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer’s disease

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660511/

      -Stephen

      Delete
  13. Also Peter, have you focused on Il-10 in the past?

    I guess bumetanide increases levels of il-10.

    https://academic.oup.com/brain/article/146/10/4247/7134130

    I've believe that il-10 is usually low in ASD kids.

    ReplyDelete
    Replies
    1. Yes, IL-10 is a key anti-inflammatory cytokine.

      Very often IL-10 is reduced and pro-inflammatory cytokines like IL-6 are elevated. It has been covered in earlier posts.

      Finding an effective immunomodulatory therapy is a key part of developing a personalized polytherapy for autism. There is no one-size-fits-all solution because there are very many sub-types of autism, but most feature a disturbed immune response of some types.

      Delete
  14. Anti-inflammatory IL-10 administration rescues depression-associated learning and memory deficits in mice

    https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-020-01922-1

    Just some food for thought.

    ReplyDelete
  15. Peter. As it's impossible for me to get bumetanide I am interested in trying Piperine on my 11 year old boy. Would you have any idea about dosage or how long to trial. I know get 10mg piperine supplements so just wondering if I just start at that see how it goes

    ReplyDelete
    Replies
    1. Piperine does cross the blood brain barrier and it does increase KCC2 expression. That does indeed make it have the potential to lower chloride in neurons, just like bumetanide.

      How much you might need to take is unknown.

      I think the important issue is how much piperine you can take without any side effects. Start with the 10mg and see how it goes.

      I have people writing to me from all over the world who have obtained bumetanide for autism (UK, USA, EU, Russia, Ukraine, China, Australia, Latin America, Middle East, Aftica etc). It certainly can be difficult, but it is possible.

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  16. https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2021.665596/full

    I only scanned through this but it appears that TRPV1 activation can enhance NKCC1 expression. In addition, it also upregulates nfkb pathway and microglial action - both of these being overactive in autism i think.

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