Showing posts with label cGP. Show all posts
Showing posts with label cGP. Show all posts

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?



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”


      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 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.


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.


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. 

Monday 30 October 2023

eIF3f-related neurodevelopmental disorder



I recently received an email from a mother in New Zealand asking about what might help her adult son, recently diagnosed with an extremely rare type of “autism” called elF3f - related neurodevelopmental disorder.

This post is just based on a preliminary investigation, I think much more would be possible if a serious full-time review was made. This applies to all the other single gene autisms that are “untreatable”.


eIF3f (eukaryotic translation initiation factor 3 subunit f)

elF3f is one of the more complicated genes/proteins with multiple functions. In layman’s terms it is involved in making all the other proteins.

eIF3f is a subunit of the eIF3 complex, hence the “f” on the end. It is required for several steps in the initiation of protein synthesis.

We saw how elF4 plays a role in how Fragile X causes intellectual disability. eIF4 is another translation initiation factor that plays a key role in the initiation of protein synthesis.

The eIF4 complex and the eIF3 complex interact with each other to form the translation initiation complex. This complex is responsible for bringing together the mRNA, the ribosome, and the initiator tRNA, which allows protein synthesis to begin.  I did warn you it gets complicated!

eIF4 and eIF3 are both essential for the initiation of protein synthesis.

eIF3f is also involved in the regulation of cell growth and proliferation, making it a target gene in cancer therapy, where eIF3f can be overexpressed or under-expressed.


In spite of what the Simon’s Foundation’s Searchlight project

Simons Search - Partnering with families. Understanding genetic changes.

Driven by science. United by hope

In order to create scientific breakthroughs for rare genetic neurodevelopmental disorders, families and scientists must come together. Simons Searchlight‘s mission is to shed light on these disorders by collecting high-quality, standardized natural history data and building strong partnerships between researchers, industry and families. Families like yours are the key to making meaningful progress.


and others say that “at this point, there are no medicines designed to treat the syndrome”, there certainly are potential treatment strategies available.

The mother did question whether there are similarities with Rett syndrome.  You can apparently reduce expression of eIF3f using the common supplement EGCG (Epigallocatechin Gallate). EGCG has been found to benefit Rett syndrome.

I think what is likely required for eIF3f-related neurodevelopmental disorder is the exact opposite, which is to increase expression of eIF3f.


Sources of data:-


GeneCards - EIF3F Gene - Eukaryotic Translation Initiation Factor 3 Subunit F

RGD - EIF3F (eukaryotic translation initiation factor 3 subunit F) Homo sapiens


The above two sites do provide a great deal of information, but I think a lot is auto-generated and there are mistakes.

What we are looking for are safe substances that change expression of the gene eIF3f.

According to GeneCards there is only one substance - quercetin.

According to RGD there is a long list.  This did look very promising, but when I looked at the linked references I did not always find that the supporting data exists.  This is a problem with AI (artificial intelligence), it can make things up.

Sometimes you have to go back to the basic science.

There is evidence that activating the PI3K/AKT/mTOR signaling pathway will increase eIF3f expression.

One known was to do that would be via increasing IGF-1 – insulin-like growth factor 1. You can inject IGF-1 and it has even been trialed in autism.

In New Zealand there is an OTC supplement called CGPMax that claims to increase IGF-1.

I checked and indeed there is some evidence that CGPMax may also increase the expression of eIF3f.

“There is some evidence that CGPMax may also increase the expression of eIF3f. In a study of ER-positive breast cancer cells, CGPMax was shown to increase the expression of eIF3f mRNA and protein. This was thought to be due to the inhibition of CDK4/6, which led to the activation of the PI3K/AKT/mTOR signaling pathway.”

AI generated

Since our reader is in New Zealand and wants a supplement rather than a drug, I think CGPMax is a good fit and certainly worth a trial.

One of the substances suggested by the RGD site was valproic acid.  This looked great news because valproic acid, an anti-epileptic drug (AED), is often used to safely treat even young children.

Why does Valproic acid apparently increase eIF3f mRNA?  That would highly likely be down to it being an HDAC inhibitor which causes it to make epigenetic changes that turn on/off our genes.

We know that some single gene autism can be treated by HDAC inhibitors, at least in mouse models. The potent HDAC inhibitors are now used to treat cancer. One parent I met at the Thinking Autism conference was desperate to access one of these potent drugs for her child’s single gene autism, similar to Kabuki syndrome.

Broccoli sprouts produce an HDAC inhibitor, called sulforaphane.

I could not find any supporting data why valproic acid was listed, the linked reference did not actually refer to eIF3f.

Nonetheless it is harmless to try broccoli sprouts.



Another common product popped up in my brief review and that was Quercetin. I had not expected to find that. There is a reaction between quercetin and eIF3f. It is not fully understood. 

Quercetin is a widely available OTC product and simple to trial.



It is known that estradiol can increase the expression of eIF3f.

The effect of estradiol on eIF3f expression is likely mediated by the estrogen receptor alpha (ERα).  We have seen that estrogen receptor beta (ERβ) is under-expressed in autism.

Increasing estradiol, or indeed reducing testosterone, has been proposed as an autism therapy. This is not a simple strategy.  In cancer therapy radical steps are taken to reduce sex hormones, because it is the only way to stop the growth of certain types of cancer.

Disturbing the level of male/female hormones will have body-wide effects.  The “men” who currently take large doses of female hormones are going to have consequences later in life.

There is dietary therapy in the form of phytoestrogens that is known to be safe.  The Japanese eat a lot of soy products.

Soy is a particularly good source of phytoestrogens, especially a type of phytoestrogen called isoflavones. Isoflavones are similar in structure to estrogen, but they are much weaker.

Incorporating more soy products into diet would seem a reasonable strategy.



There is some evidence that the antibiotic gentamicin can activate the gene eIF3f.  It is given by injection.

Among the list of substance that can increase eIF3f mRNA are some quite toxic substances like BPA found in plastic packaging.  Another interesting option was listed under “anti-rheumatic drugs”, this actually refers to tocilizumab. This is an anti-arthritis drug given to people over the age of two.  Since it ends in -mab, we can infer that it contains monoclonal antibodies, in this case to interleukin-6.

Tocilizumab would likely be helpful in many people with other kinds of autism with a strong auto-immune component.


eIF3f-specific treatments vs treat as idiopathic autism

We know from readers with children with different single gene autisms, that are supposed to be untreatable, that these children often respond well to therapies in use for autism of unknown origin (idiopathic autism).

Almost all autism features neuroinflammation, activated microglia etc. Most autism features oxidative stress.  Most autism features impaired myelination. Much autism features mitochondrial dysfunction.

There are specific insights that a genetic diagnosis does give you.  In the case of eIF3f, we are dealing with hypo-active (REDUCED) pro-growth signaling. That means the opposite to the kids born with macrocephaly (big heads).


This excellent framework was explained in this old post

IGF-1 was mentioned earlier as a possible therapy.  Note that growth hormone (GH) is made in the anterior pituitary gland, it is released into the blood stream, and then stimulates the liver to produce IGF-1. IGF-1 then stimulates systemic body growth, and has growth-promoting effects on almost every cell in the body.

More IGF-1 would lead to more growth. Even in an adult you can increase the density of dendritic spines.

As shown in the chart above on the lower right, in today’s disorder we have decreased protein synthesis.

Now back to the science and the basics of this syndrome. 

eIF3f-related neurodevelopmental disorder (EIF3F-RND) is a rare genetic disorder that causes a variety of neurological and developmental problems. It is caused by mutations in the eIF3f gene, which provides instructions for making a protein that is involved in protein synthesis. It has to be inherited from both parents.

If both parents are carriers, there is a 25% chance that each child will have EIF3F-RND, a 50% chance that each child will be a carrier, and a 25% chance that each child will not have EIF3F-RND and will not be a carrier.

If only one parent is a carrier of the mutated gene, there is a 50% chance that each child will be a carrier, and a 50% chance that each child will not be a carrier and will not have EIF3F-RND.

The incidence of EIF3F-related neurodevelopmental disorder (EIF3F-RND) is unknown. However, it is estimated to be a very rare disorder, affecting less than 1 in 100,000 people. This is likely due to the fact that EIF3F-RND is caused by mutations in a single gene. In order for a child to be affected, both parents must carry a copy of the mutated gene. If only one parent is a carrier, the child will be a carrier, but will not be affected.

The incidence of EIF3F-RND may also be underestimated, as it is a relatively newly identified disorder. As more people are diagnosed with the disorder, the incidence rate may increase. 

EIF3F-RND is caused by under-expression of the eIF3f protein.

Symptoms of EIF3F-RND can vary widely from person to person, but may include:

  • Intellectual disability
  • Developmental delay
  • Seizures
  • Hypotonia (low muscle tone)
  • Microcephaly (small head size)
  • Autism spectrum disorder
  • Facial dysmorphism





Interactions with other genes/proteins 

One feature of the GeneCards website is that you can see a representation of which are the most important interactions of a gene/protein.

This can sometimes suggest a possible therapy, since one of these related genes might be easier to treat.

In the case of eIF3f almost all the interactions are with other elF-somethings.

The RPS-somethings below are all genes that translate mRNA into proteins.

So, everything below is part of the machinery cells have to make proteins.




EIF3F-related neurodevelopmental disorder research

The EIF3F-NDR research is still in its infancy.

There need to be a models made that can suggest which downstream genes are affected and hence might be treatable.

An eIF3f activator is a drug or other compound that can increase the expression or activity of the eIF3f protein.

Currently, there are no known eIF3f activators that are approved for clinical use. However, researchers are developing a number of different approaches to activating EIF3F, including:

  • Small molecule drugs: Researchers are screening libraries of small molecules to identify compounds that can bind to eIF3f and increase its activity.
  • Gene therapy: Gene therapy could be used to deliver a working copy of the eIF3f gene to cells in the nervous system.
  • CRISPR gene editing: CRISPR gene editing could be used to correct mutations in the eIF3f gene.

In addition to the above approaches, there are a number of other things that could potentially be done to activate eIF3f, such as:

  • Identifying and targeting upstream regulators of eIF3f: Researchers could identify and target other proteins or genes that regulate the expression or activity of eIF3f. This could lead to the development of new drugs or other therapies that could be used to activate eIF3f indirectly.
  • Understanding the role of eIF3f in different cell types: Researchers are still learning about the role of eIF3f in different cell types in the nervous system. This knowledge could be used to develop targeted therapies that activate eIF3f in the specific cell types where it is needed most.


EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum



An identical homozygous missense variant in EIF3F, identified through a large-scale genome-wide sequencing approach, was reported as causative in nine individuals with a neurodevelopmental disorder, characterized by variable intellectual disability, epilepsy, behavioral problems and sensorineural hearing-loss. To refine the phenotypic and molecular spectrum of EIF3F-related neurodevelopmental disorder, we examined independent patients.


21 patients were homozygous and one compound heterozygous for c.694T>G/p.(Phe232Val) in EIF3F. Haplotype analyses in 15 families suggested that c.694T>G/p.(Phe232Val) was a founder variant. All affected individuals had developmental delays including delayed speech development. About half of the affected individuals had behavioral problems, altered muscular tone, hearing loss, and short stature. Moreover, this study suggests that microcephaly, reduced sensitivity to pain, cleft lip/palate, gastrointestinal symptoms and ophthalmological symptoms are part of the phenotypic spectrum. Minor dysmorphic features were observed, although neither the individuals’ facial nor general appearance were obviously distinctive. Symptoms in the compound heterozygous individual with an additional truncating variant were at the severe end of the spectrum in regard to motor milestones, speech delay, organic problems and pre- and postnatal growth of body and head, suggesting some genotype–phenotype correlation.


Our study refines the phenotypic and expands the molecular spectrum of EIF3F-related syndromic neurodevelopmental disorder.


The cancer research

Cancer research is much more advanced and better funded than autism research.

As you can see in the table below, decreased expression of eIF3f is feature of several common cancers. If you can upregulate eIF3f you might have a viable cancer therapy.

As in many types of autism, the potential exists to repurpose cancer drugs as and when they get developed and approved. HDAC inhibition is perhaps the best example. So far people are too scared to try the new potent HDAC inhibitors in human single-gene (monogenic) autism.


Alternatively, an indirect regulation of the activity of eIF3 is performed by association of its subunits with other proteins involved in the regulation of protein synthesis. For example, the subunit eIF3e binds p56 in interferon-treated or virus-infected mammalian cells, and inhibits the translation in vitro and in vivo [43, 44]. The subunit eIF3g interacts with Paip1, a Poly (A)-binding protein and stimulates translation initiation [45] whereas the subunits eIF3h and eIF3f interact with TRC8, a ubiquitin E3 ligase, and inhibit protein synthesis, possibly through ubiquitilation of eIF3 or some other translational components [46]. These mechanisms and interacting partners render eIF3 a pivotal player in controlling the protein synthesis and degradation. 

All these data confirm that eIF3f has a multileveled control of multiple functions in the cells, outside its usual function in translation. Keeping it in mind, targeting eIF3f may be a strategy to reorganize different intracellular pathways and alter the basis of the balance between cell proliferation and apoptosis. Thus, eIF3f represents a lead candidate to use for biotherapeutic applications both for inhibiting the growth of cancer cells or muscle atrophy and thus preventing its progression into irreversible cachexia.



Personally, I would treat EIF3F-NDR with two parallel approaches:

·        As idiopathic autism with hypo-active pro-growth sigaling autism (small heads/microcephaly)

·        Gene specific with clever ideas targeting the effects of eIF3f under-expression.

Is the cognitive impairment responding to bumetanide?  In the models of Rett syndrome and Fragile-X this is the case. For EIF3F-NDR you could just make your own trial.

For sure there will be oxidative stress in EIF3F-NDR due to the malfunctioning in the protein synthesis “machinery”.  NAC is the antioxidant of choice and is OTC.

EIF3F-NDR can be associated with GI dysfunction, as is much of broader autism.  When treated this often leads to improvements in behavior.

Increasing IGF-1 looks achievable.

Nerve growth factor (NGF) may be upregulated by Lion’s Mane mushrooms, according to the research.

BDNF (brain derived neurotropic factor) can be up regulated. Certain foods and nutrients have been shown to increase BDNF levels. For example, one study found that lutein supplementation increased BDNF levels in the blood. Other foods and nutrients that have been shown to increase BDNF levels include omega-3 fatty acids, magnesium, and zinc.  Some drugs increase BDNF such as lithium, SSRIs, modafinil. Statins such as Simvastatin and Atorvastatin are known to increase BDNF.



Wednesday 21 September 2022

Pentoxifylline and cGP (an IGF-1 normalizer) from Blackcurrants, for Autism?



Readers may be wondering at what point Peter will run out of things to write about.  I do sometimes wonder the same thing. I was going to also write about Loperamide (Imodium), but the post would have been too long. Next time!


Pentoxifylline has been in use to treat autism for 50 years. The original studies did suggest its effect was greatest among small children.  I have been in some discussions with a US psychiatrist, Dr Powell, who is a big fan of the off-label use of this drug to affect the brain in adults.  He has even written a book on the subject.

My previous posts on Pentoxifylline can be found here:

Dr Powell’s patients with autism tend to be older children, not the toddlers who did well in clinical trials in Japan in the 1970s.  He sees significant improvement in many, but not all, of his patients with autism.  The parents report improved social interactions and having higher-level discussions with their child.

What is notable is that he uses frequent dosing, 4 times a day, always after food to avoid the GI side effects.

Pentoxifylline is inexpensive, but its effect does not last long, hence the frequent dosing.  Some people take taking this drug 5-6 times a day.

Pentoxifylline has multiple modes of action, it should increase blood flow to the brain and it is broadly anti-inflammatory.  It is a non-selective PDE inhibitor, normally used treat muscle pain in people with peripheral artery disease. It increases red blood cell flexibility and it reduces the viscosity of blood.

There are PDEs 1 to 11. It all gets quite complicated, for example PDE1 subtype A2 has a potential role in neurodegenerative diseases, including:

·        Parkinson's disease

·        Axonal neurofilament degradation

·        Motorneuronal degradation

·        Neuronal ischemia

·        Alzheimer's disease

·        Epilepsy

Recall that PDE4 inhibitors are used to treat asthma and COPD. We can potentially repurpose those to improve myelination in MS, or autism, and at specific low doses they can improve cognition.


cGP (from Black Currants)

I did write quite a lot in this blog about growth factors and autism.  The familiar ones are BDNF, NGF and IGF-1, but there are many more. 

My previous posts on IGF-1 can be found here:

We know that growth signaling in autism is disturbed, but it is not simple.  As the disease progresses (the fetus develops, the baby is born and grows into a toddler) the imbalance in growth signaling changes.  This means that what would be helpful in a 6 month old baby might well be inappropriate in a 6 year old.  This is a good example of what I call the what, when and where of treating autism. Here it is the “when” that matters.

Some people lack BDNF while others have too much. Very possibly, this changes over time in the same child.

One possible therapy for autism is injections of IGF-1 (Insulin-like Growth Factor 1).  IGF-1 plays an important role in childhood growth.

A synthetic analog of IGF-1 is used in children for the treatment of growth failure.  This drug called Mecasermin was used in autism trials and in Rett syndrome trials.

In Rett syndrome the search has been on for an oral therapy.

Trofinetide (NNZ-2566) is a potential therapy for Rett syndrome being developed by Neuren Pharmaceuticals in Australia.

Trofinetide is derived from IGF-1.

Trofinetide got to phase 2 trials as a therapy for Fragile-X in 2015.

The second product in development at Neuren is NNZ-2591.  It is aimed at normalizing the level of IGF-1.

This is in the pipeline to treat:

  • Phelan-McDermid syndrome (Shank3 gene and others not working)
  • Angelman syndrome (UBE3A gene not working)
  • Pitt Hopkins syndrome (TCF4 gene not working)
  • Prader-Willi syndrome (MAGEL2 gene and others not working)


What is NNZ-2591?

It is an analogue (modified version) of cyclic glycine proline (cGP)

Cyclic glycine-proline (cGP), a metabolite of IGF-1, is neuroprotective through improving IGF-1 function.

There is also research focused on Parkinson’s and Alzheimer’s where it seems that cGP is reduced.

In New Zealand they found that supplementation of Blackcurrant anthocyanins (pigments) increased cGP in the spinal fluid of patients with Parkinson’s.

This also led the way to the idea of increasing cGP as means of protecting the brain during aging. There is now a commercial OTC product in New Zealand to do just this.

Our reader Daniel, who has a daughter with Rett syndrome, is assessing the benefit of cGP, using the OTC product cGPMAX. The results so far are promising.

Rett is very specific because we know for sure that IGF-1 and NGF are disturbed.

Is cGP going to be beneficial in broader autism?  May be yes, but we come back to the what, when and where.  It may well depend on when a specific person takes it.  We have both hypoactive pro-growth signalling autism and hyperactive pro-growth signalling autism.



Unfortunately, what the clever researchers who came up with the above concept did not consider is that you may start out hyper in the womb and switch to hypo a few short years later.



Frequently dosed Pentoxifylline looks like a potentially interesting therapy for many with autism, including some with high IQ.  Take note our Aspie readers.

Daniel’s idea to look at the Neuren’s non-Rett therapy as a Rett therapy is interesting.  In effect you do not need to wait for the Australian drug, you can hop across the Tasman Sea to New Zealand and use their cGP supplement, developed for protection against dementia.

You would also think that parents of children with:

  • Phelan-McDermid syndrome (Shank3 gene and others not working)
  • Angelman syndrome (UBE3A) gene not working)
  • Pitt Hopkins syndrome (TCF4 gene not working)
  • Prader-Willi syndrome (MAGEL2 gene and others not working)

might want to follow Daniel’s lead.

As you can see, there is a lot of trial and error in science.  Back in 2009 NNZ-2566 was in clinical trials for the treatment of cognitive deficits following traumatic brain injury.  That must not have worked out.  Fragile-X did not work out and now it is phase 3 for Rett girls, which seems to be going well.


IGF-1 for old people

The same growth factor IGF-1 that is key during development also plays a key role in aging. Dr Jian Guan made a world first discovery. She discovered that cGP (cyclic Glycine-Proline) was responsible for controlling the IGF-1 hormone in our body. Thus by increasing the level of cGP in our body, the cGP will essentially command the IGF-1 to build more blood vessels.

Dr Jian Guan, was then recognised as the world-wide authority on cGP. In 2017 she discovered that New Zealand blackcurrants contained high volumes of natural cGP which could regulate optimum levels of IGF-1 in the body.

So now we have Antipodeans/Kiwis fending off dementia, and potentially metabolic syndrome, by taking their locally made cGPMax.

Will it help you case of autism? Who knows, but if it does not, just give the leftover pills to Grandma, Granddad or take them yourself!


All the supporting papers from New Zealand.