Facilitated Communication leading to Un-facilitated Communication?

I am surprised how many people with level 3 autism reach adulthood without a means of communication. By that I mean any means of communication, such as:

·        Sign language

·        PECs

·        Augmentative and Alternative Communication (AAC) devices

·        An iPad

·        Writing by hand

·        Typing on a keyboard

·        Talking

You would think that in special schools around the world children would all be taught some method of communication. After all, they have 8 hours a day for 12-15 years to do it.

I am surprised that even in the US and Canada this is not the case. In most of the world special education has much less funding and it is of no surprise that what learning does occur mostly takes place at home.

I was recently going through my book collection, making some notes for what might be useful for my own upcoming book.

When it comes to autism books, I have a couple written by doctors with their treatment ideas. I do like Dr Chez and did buy his book; some readers of this blog do consult him.

I also have a copy of Dr Bryan Jepson’s book, I only skimmed through it.  He has two autistic children, one adopted, and used to work at Thoughtful House in Atlanta, where Dr Wakefield took a position after quitting the UK.  I was curious what happened to Dr Jepson. He went back to being a regular doctor.  His two sons are now adults living at home with him, both are non-verbal and both can be aggressive.  In many ways that sounds like an aging parent’s worst nightmare.  The good news is that both learned to communicate, one can type his thoughts and the other communicates via an iPad.  What I found interesting was that the communication breakthrough did not come at school, but rather courtesy of Soma Mukhopadhyay and her facilitated communication program in Austin, called the rapid prompting method (RPM).  Many parents of kids/adults with severe autism really trash facilitated communication.

The point here is that facilitated communication opened the door to un-facilitated communication.  This is a key point.  If you can never fade the prompting/facilitation, it is not really communication, it is wishful thinking.

I was looking around the house for a copy of the Reason I Jump, this book was written by the mother of a Japanese boy with autism, based on what she interpreted him wanting to say by pointing at a letter board.

There is a follow up book to the Reason I Jump, but is it the mother’s work or her son’s? 

One of Jepson’s sons writes poetry.  Since he can now type, I assume this is 100% his work.  I guess this is in large part down to his work with Soma Mukhopadhyay.

 

Fading the prompt

Parents and 1:1 teaching assistants are naturally protective and this can end up with them giving too much help.  The learner then becomes prompt dependent.

If you never let the learner try a task unassisted, how will he ever truly master it?

I am trying to get Monty, now aged 19 with what was level 3 autism, to be more independent.

Recently I took him about 3 miles (4km) from home to a very familiar place.  He had his electric scooter and I asked him to scoot home.  He set off with me following on foot. I half expected him to stop at the first road junction and wait for me, but just scooted all the way home, crossing several roads.

I repeated the same exercise with different start points and each time he made it home with no problems.  I did observe how he crossed roads and he was very responsible.

Some people did think I was mad, but it turned out that I was not.

 

Teaching someone with level 3 autism to read and write

Learning to read and write is not a challenge for a child with normal IQ who already knows how to speak.  Teaching a non-verbal or minimally verbal child to read and write is usually a great challenge and not one to be left to school.  It can take a vast amount of time and effort. This is not something parents ever expected to be responsible for.  Some rise to the challenge and some do not.

I am sure there are some very good schools where they make huge efforts and achieve great results.  15 years ago I went on a 3 day course to learn how to teach the picture exchange communication system (PECs). There were a few teaching assistants in the group and a couple of parents, the rest were speech therapists and the like.

The thing parents do not realize is just how much time an effort it can take to apply these methods. An hour or two with a speech therapist is not going to make an impact. 

I just read about one parent saying that their speech therapist is trying to teach their child using picture cards. Can he reliably identify the card with a tree when presented with 2 or 3 alternatives? Why is someone paying $60 an hour for a speech therapist to do this?  It can all be done at home with a touchscreen and an app.  I was doing this early in the mornings 15 years ago when Monty with 4 years old.  We spent hundreds of hours doing exercise like this, practising nouns, verbs, categories and other exercises. Toddlers with autism learn by repetition, which can feel like a never-ending process.  The time invested does pay off.     

Once you have learned words using pictures, you can then learn to recognise the written words. These are like sight words.

Then you can learn the alphabet, phonics and spelling.

Then you have the task of putting all this together into actual reading and writing.

Once you can read, the question is whether you actually understood anything.

It can be a painfully slow process, but time is something you have plenty of.

 

Monty 

Monty reads almost every day for about 30 minutes. The long running question was how much he actually understands.

The same issue used to arise when he saw a film in the cinema, how much really had sunk in?

Interestingly, when Monty is asked to what he did at the weekend he makes only a brief verbal reply, but when asked to write about it, he will sit down and neatly write 500 words. If he went to see a film, he will now include a summary of the story.

 

Conclusion

Whatever method you chose that ultimately leads to independent communication was the right one.

If it works, it works.  Whatever anyone else has to say about the method really does not matter.   

Calcium channelopathies and intellectual disability

 

Changsha, another big city in China you probably have not heard of

 

Today’s post follows up on the use of calcium channel blockers to treat autism.  This is a subject that I first looked at in this blog several years ago.  One of our readers even wrote a book entirely about this subject.

There has been plenty of research going back a decade or more, but no effort to translate it into common therapy.

By coincidence, one reader recently sent me a list of about 20 suspect genes from her daughter’s tests. 7 are related to just a pair of L-type calcium channels, the suggested action was to take magnesium sulfate. I referred her back to my old posts, particularly since her main concern is self-injury. I have written a great deal about Cav1.2 and self-injury, since it is treatable using Verapamil. 

I think a better interpretation of the genetic testing results would have been to say possible channelopathies in Cav1.2 and Cav1.3.  Given that mutations usually lead to over expression of ion channels, a likely effective therapy would be to block these channels.

Magnesium does act as a calcium channel blocker, among its very many other effects.

Is magnesium sulfate the best choice of Cav1.2 and Cav1.3 blocker?  I doubt it, but at least it is OTC. 

 

Treating Intellectual Disability (ID) rather than Autism

I do often think that we should be talking more about treating ID rather than autism.

Who would object to treating ID? Hopefully nobody.

Today’s paper is about treating intellectual disability (ID) and global developmental delay (GDD).

Almost all people with level 3 autism could also be described as ID + GDD.

Level 3 autism = ID + GDD

We also have IDD which is Intellectual and Developmental Disability.

Too many names for the same thing, if you ask me.

The paper below from Changsha, China starts with the hypothesis that:-

Calcium Channels play a major role in the development of ID/GDD and that both gain- and loss-of-function variants of calcium channel genes can induce ID/GDD.

The paper is published in the  Orphanet Journal of Rare Diseases.

2.3% of the general population have an IQ less than 70 and so have intellectual disability (ID).  ID is not really rare. More than 1 million people in the United States have intellectual disability (ID). 

There are many different processes involved in intellectual disability (ID).  On the one hand that makes it complicated, but on the other hand that means there are many options beyond just L-type calcium channels blockers.

The paper below is really only looking and at Cav1.2 and Cav1.3.  As I pointed out in my previous post, there is much more to it than just this pair.

On the bright side, at least some people in China are looking at this.

  

Calcium channelopathies and intellectual disability: a systematic review

Background

Calcium ions are involved in several human cellular processes including corticogenesis, transcription, and synaptogenesis. Nevertheless, the relationship between calcium channelopathies (CCs) and intellectual disability (ID)/global developmental delay (GDD) has been poorly investigated. We hypothesised that CCs play a major role in the development of ID/GDD and that both gain- and loss-of-function variants of calcium channel genes can induce ID/GDD. As a result, we performed a systematic review to investigate the contribution of CCs, potential mechanisms underlying their involvement in ID/GDD, advancements in cell and animal models, treatments, brain anomalies in patients with CCs, and the existing gaps in the knowledge. We performed a systematic search in PubMed, Embase, ClinVar, OMIM, ClinGen, Gene Reviews, DECIPHER and LOVD databases to search for articles/records published before March 2021. The following search strategies were employed: ID and calcium channel, mental retardation and calcium channel, GDD and calcium channel, developmental delay and calcium channel.

 

Main body

A total of 59 reports describing 159 cases were found in PubMed, Embase, ClinVar, and LOVD databases. Variations in ten calcium channel genes including CACNA1A, CACNA1C, CACNA1I, CACNA1H, CACNA1D, CACNA2D1, CACNA2D2, CACNA1E, CACNA1F, and CACNA1G were found to be associated with ID/GDD. Most variants exhibited gain-of-function effect. Severe to profound ID/GDD was observed more for the cases with gain-of-function variants as compared to those with loss-of-function. CACNA1E, CACNA1G, CACNA1F, CACNA2D2 and CACNA1A associated with more severe phenotype. Furthermore, 157 copy number variations (CNVs) spanning calcium genes were identified in DECIPHER database. The leading genes included CACNA1C, CACNA1A, and CACNA1E. Overall, the underlying mechanisms included gain- and/ or loss-of-function, alteration in kinetics (activation, inactivation) and dominant-negative effects of truncated forms of alpha1 subunits. Forty of the identified cases featured cerebellar atrophy. We identified only a few cell and animal studies that focused on the mechanisms of ID/GDD in relation to CCs. There is a scarcity of studies on treatment options for ID/GDD both in vivo and in vitro.

 

Conclusion

Our results suggest that CCs play a major role in ID/GDD. While both gain- and loss-of-function variants are associated with ID/GDD, the mechanisms underlying their involvement need further scrutiny.

 

Discussion

Overall, this condition seems to be progressive, however, most primary authors provided less information on the course of the disease. Many of the reported cases with electrophysiological studies had gain-of- function variants. Severe to profound ID/GDD was more predominant for the cases with gain-of-function variants as compared to those with loss-of-function. CACNA1E, CACNA1G, CACNA1F, CACNA2D2 and CACNA1A associated with more severe phenotype. The possible reasons as why these genes associated with more severe phenotype include (1) the neuronal location of the genes; all of them are located in the pre-synaptic membrane, (2) brain distribution; most of them are distributed in the brain cortex and/or hippocampus and/or cerebellum, (3) function of the genes; they all regulate the release of neurotransmitter, and (4) the effect of the variants; most of the reported variants in these genes had gain-of-function property. This review has also revealed some hotspots for future research.

  

Conclusion

Gain of function of Cav1.2 and Cav1.3 continues to be well documented in the literature.  That means too much calcium (Ca²⁺ ) entering neurons, from outside.

Note that inside cells/neurons you have a store of Ca²⁺ in something called the Endoplasmic Reticulum (ER). There is supposed to be a high level of Ca²⁺ inside the ER.  When things go wrong, there can be ER stress and Ca²⁺ may get pushed out, or too much Ca²⁺ may be let in. ER stress plays a role in many diseases including autism. In autism the channel implicated is called IP3R. ER stress ultimately leads to cell death. This is the mechanism behind how people with diabetes stop producing insulin. ER stress in the beta cells in their pancreas caused the beta cells to die. No beta cells means no insulin. In such people very prompt treatment by blocking Cav1.2 stops the beta cells dying.

The people seeing a benefit from blocking Cav1.2 and/or Cav1.3 in someone with autism, ID, IDD, GDD, ADHD, epilepsy, SIB, or chronic headaches etc, have science on their side.  It is not just Chinese science; it is science from everywhere.

Note that ion channel dysfunctions can be genetic (they show up on genetic tests) or they can be acquired (they do not show up on testing).

The open issue is what is the most effective therapy.  This is going to vary from person to person, but it is unlikely to be magnesium sulfate.

Magnesium is an important mineral to get from a healthy diet, but it has many effects including blocking NMDA receptors.  This effect might be good or it might be bad. High doses of magnesium supplements will cause GI problems. Most people lack magnesium so a little extra would seem fine, but using enough to block calcium channels may not be wise.

Blocking Cav1.3 will Amlodipine should be the subject of a clinical trial.

Blocking Cav1.2 with Verapamil should be the subject of a clinical trial.

Maybe in China?

Different L-type Calcium Channel Blockers Repurposed for Different Types of Autism

 

 A Purkinje Neuron, home of P-type calcium channels

Today’s post was prompted by a reader who saw a very positive response from the L-type calcium channel blocker, Amlodipine.

So we return to the subject of calcium channels.

The good news about calcium channel defects is that many are easy to treat.

In most single gene autisms (Rett, Fragile-X, Pitt Hopkins etc) the underlying problem is that a faulty gene does not do its job of producing the expected protein.  This is a problem of too little.

In many ion channel dysfunctions the problem is not too little, it is too much expression. For example, in Timothy Syndrome the mutation in the gene produces too much of the protein, in this case the L-type calcium channel Cav1.2.

Ion channel dysfunctions can be the result of a faulty gene, or just that the on/off switch for that gene is faulty.  Fortunately, the problem is usually that it is stuck “on”.

In people who develop Type-1 diabetes we have seen how the disease process can be halted by blocking Cav1.2 in the pancreas.  This halts the decline in the beta cells that produce insulin.

Once all the beta cells are dead, the person cannot produce insulin and has type-1 diabetes. Treating the person after this point with a Cav1.2 blocker will provide no benefit; the damage has already been done

Something similar happens in Parkinson’s disease, but this time you need to block Cav1.3.  In the early stages of the disease Cav1.3 is over-expressed in a key part of the brain, which triggers a slow process of degeneration. Treating a person with all the visible symptoms of Parkinson’s with a Cav1.3 blocker will provide no benefit; the damage has already been done.

 

Calcium channel blockers are not very specific

The current drugs used to block calcium channels were mainly developed to treat heart conditions.

When treating neurological disorders like autism we are primarily focused on the brain, what goes on elsewhere can also be very relevant, but in an indirect way.

In the brain the important calcium channels are: -

L type

N type

P type

R type

T type

Plus, Inositol trisphosphate receptor (IP3R) and Ryanodine receptors. IP3R has been covered in previous posts.

Verapamil (a Phenylalkylamine class drug)

Verapamil blocks L type channels and T type channels, plus some potassium ion channels.

When it comes to specific L type channels there are 4, Cav1.1, Cav1.2, Cav1.3, and Cav1.4.

In the brain we have just Cav1.2 and Cav1.3. Verapamil mainly affects Cav1.2.

 

Amlodipine (a Dihydropyridine class drug)

Amlodipine blocks L type channels and N type channels.

Amlodipine mainly affects Cav1.3.

 

Nicardipine (a Dihydropyridine class drug)

Nicardipine blocks L type channels and N type channels.

As a Dihydropyridine, it should mainly affect Cav1.3.

In addition, it blocks the sodium ion channel Nav1.8.

The effect on Nav1.8 is why it has been proposed as a therapy for Pitt Hopkins. In this syndrome Nav1.8 is over expressed as a downstream consequence of a mutation in the TCF4 gene.

 

Effect on P channels

To some extent Verapamil, Amlodipine and Nicardipine all block P channels.

P channels are called P after the Purkinje neurons, where they are located. These Purkinje cells likely define some aspects of autism, because of their absence. Purkinje neurons are among the largest in the brain, with elaborate dendritic arbor.  I imagine this makes them vulnerable.

In the people with severe autism most of the Purkinje cells appear to have died.

Blocking P channels might have protected Purkinje cells from death.

 

The effect of too much L-type calcium channel signaling on behavior 

You can both turn on self-injury via activating L type calcium channels and extinguish it by blocking the same channels.  It is proven in mice and seems to apply to at least some humans.

Calcium channel activation and self-biting in mice

The L type calcium channel agonist (±)Bay K 8644 has been reported to cause characteristic motor abnormalities in adult mice. The current study shows that administration of this drug can also cause the unusual phenomenon of self-injurious biting, particularly when given to young mice.

The self-biting provoked by (±)Bay K 8644 can be inhibited by pretreating the mice with dihydropyridine L type calcium channel antagonists such as nifedipine, nimodipine, or nitrendipine. However, self-biting is not inhibited by nondihydropyridine antagonists including diltiazem, flunarizine, or verapamil.

(±)Bay K 8644 functions as an L type calcium channel activator that increases calcium fluxes in response to depolarizing stimuli (19–21). In rodents, this drug has been reported to produce characteristic motor abnormalities including impaired ambulation, twisting and stretching movements, transient limb extension, back arching, spasticity, ataxia, or catatonia (22–28). Some studies have anecdotally noted the occurrence of SIB with this drug (23–25, 27), though this phenomenon has received little attention. The current study shows that (±)Bay K 8644 will reliably provoke SB and SIB under certain conditions in mice, providing a tool to study the neurobiology of this unusual behavior.

 

When I first encountered the above study, I did wonder why Verapamil did not extinguish the self-injury.

It turns out that Bay K 8644 is a modified version of the common drug nifedipine, which is a Cav1.3 blocker.  Verapamil is mainly a Cav1.2 blocker.  Bay K 8644 is like the opposite of nifedipine.

In the trial they have activated Cav1.3 causing excess calcium inside neurons. The only way to block this process is to block Cav1.3. Blocking Cav1.2 with Verapamil could not solve the problem. 

Note that activation of Cav1.3 can cause motor abnormities in mice and this might be seen as ataxia in a human. One particular reader of this blog will see the relevance of this. 

I did write extensively in earlier posts about the large amount of research that links L type calcium channels to neuropsychiatric disorders.

I did mainly focus on Cav1.2 using Verapamil, but the evidence for the role of Cav1.3 is clear as day. 

L-type calcium channels as drug targets in CNS disorders

 L-type calcium channels are present in most electrically excitable cells and are needed for proper brain, muscle, endocrine and sensory function. There is accumulating evidence for their involvement in brain diseases such as Parkinson disease, febrile seizures and neuropsychiatric disorders. Pharmacological inhibition of brain L-type channel isoforms, Cav1.2 and Cav1.3, may therefore be of therapeutic value.

 

From Gene to Behavior: L-Type Calcium Channel Mechanisms Underlying Neuropsychiatric Symptoms.

The L-type calcium channels (LTCCs) Ca_v1.2 and Ca_v1.3, encoded by the CACNA1C and CACNA1D genes, respectively, are important regulators of calcium influx into cells and are critical for normal brain development and plasticity. In humans, CACNA1C has emerged as one of the most widely reproduced and prominent candidate risk genes for a range of neuropsychiatric disorders, including bipolar disorder (BD), schizophrenia (SCZ), major depressive disorder, autism spectrum disorder, and attention deficit hyperactivity disorder.

Here, we provide a review of clinical studies that have evaluated LTCC blockers for BD, SCZ, and drug dependence-associated symptoms, as well as rodent studies that have identified Ca_v1.2- and Ca_v1.3-specific molecular and cellular cascades that underlie mood (anxiety, depression), social behavior, cognition, and addiction.

 

Was I surprised that Amlodipine, that targets Cav1.3 rather than Cav1.2, was very beneficial in someone with severe autism?  Not at all.

I was interested that the effect was more pro-cognitive than anti-anxiety.  Is that the effect on Cav1.3 or is it via that N channel Cav2.2?

N-type calcium channels are important in neurotransmitter release because they are localized at the synaptic terminals. Piracetam, the original cognitive enhancing drug, is also a N type channel blocker.

  

Statins and L type calcium channels blockers – it matters which one you choose

We previously saw how the statin class of drugs can be beneficial in autism, but it depends which one you chose. For example, in SLOS (Smith-Lemli-Opitz syndrome), where both copies of the gene DHCR7 are mutated, you need to push the gene to work. To increase expression of this gene you need Simvastatin. This is hard for people to understand because SLOS features very low cholesterol and statins are thought of as cholesterol lowering drugs. The body needs the enzyme DHCR7 to make cholesterol and Simvastatin increases DHCR7 expression.

In the case of L type channel blockers, the selection is very important.  The effect will not be the same.

If you have a mutation in Cav1.2, you would expect Verapamil to be a good choice.  If the mutation is in Cav1.3, you would expect Amlodipine to be better.

If you have over expression of T channels (Cav3.1, Cav3.2 or Cav3.3) then you would expect a benefit from Verapamil and none from Amlodipine.

If you have over expression of the N channel (Cav2.2) then you would want Amlodipine

If you have over expression of the sodium channel Nav1.8 then you would want Nicardipine

  

Conclusion

It is likely that many people with autism, bipolar, ADHD or schizophrenia might benefit from treating their ion channel dysfunctions.  The required drugs are cheap generics that have been in your local pharmacy for a few decades.

Back in 2019 I wrote the post below:

Cheap common drugs may help mental illness

I highlighted a new study, using historic data from Sweden, that looked at the secondary effects of statins, calcium channel blockers and metformin on psychiatric hospitalization.

 

Association of Hydroxylmethyl Glutaryl Coenzyme A Reductase Inhibitors, L-Type Calcium Channel Antagonists, and Biguanides With Rates of Psychiatric Hospitalization and Self-Harm in Individuals With Serious Mental Illness

 

Question  Are drugs in common use for physical health problems (hydroxylmethyl glutaryl coenzyme A reductase inhibitors, L-type calcium channel antagonists, and biguanides) associated with reduced rates of psychiatric hospitalization and self-harm in individuals with serious mental illness?

Findings  In this series of within-individual cohort studies of 142 691 patients with bipolar disorder, schizophrenia, or nonaffective psychosis, exposure to any of the study drugs was associated with reduced rates of psychiatric hospitalization compared with unexposed periods. Self-harm was reduced in patients with bipolar disorder and schizophrenia during exposure to all study drugs and in patients with nonaffective psychosis taking L-type calcium channel antagonists. 

We found that periods of HMG-CoA RI (statin) exposure were associated with reduced psychiatric hospitalization in all subgroups of SMI (Serious Mental Illness) and with reduced self-harm in BPD and schizophrenia.

Exposure to LTCC (L type calcium channel) antagonists was associated with reduced rates of psychiatric hospitalization and self-harm.

Periods of metformin (a type 2 diabetes drug) exposure were associated with reduced psychiatric and nonpsychiatric hospitalization across all SMI subgroups.

 

Use of L type calcium channel blockers reduces self-harm.

How much more evidence is needed?

I took an educated guess several years ago that Verapamil would tame summertime raging in my son.  It was the only calcium channel blocker I tried and it worked. This year we had the emergence of extreme sound sensitivity. My educated guess was that blocking potassium channels with Ponstan (Mefenamic acid) would resolve the problem, and it did.  

Treating ion channel dysfunctions (channelopathies) in autism clearly is not rocket science; it is just waiting to be attempted.

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