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

Monday 30 October 2023

eIF3f-related neurodevelopmental disorder

 


Source: https://ojrd.biomedcentral.com/articles/10.1186/s13023-021-01744-1/figures/2


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

https://www.genecards.org/cgi-bin/carddisp.pl?gene=EIF3F

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

https://rgd.mcw.edu/rgdweb/report/gene/main.html?id=1314535

 

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.

 

Quercetin

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.

 

Estradiol

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.

 

Others

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

https://www.epiphanyasd.com/2015/12/one-of-thousands-autism.html

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

 

 



Source: https://ojrd.biomedcentral.com/articles/10.1186/s13023-021-01744-1/figures/2

 

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

 

Background

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.

Results

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.

Conclusions

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.

  

https://theses.hal.science/tel-01679873/document



 


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.

 

Conclusion

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

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: 

https://www.epiphanyasd.com/search/label/Pentoxifylline

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: 

https://www.epiphanyasd.com/search/label/IGF-1

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)

https://www.neurenpharma.com/irm/content/product-development-pipeline.aspx?RID=483&RedirectCount=1

 

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.

  

Conclusion

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.

https://cgpmax.com/pages/our-science