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Showing posts with label NNZ-2566. Show all posts
Showing posts with label NNZ-2566. Show all posts

Thursday, 28 April 2016

Intranasal Insulin for Some Autism vs IGF-1 and NNZ-2566

 

Very often the simplest solutions are the best and very often, when fault finding a problem, people overlook the obvious.  

I seem to be forever having to mend things and I find this all the time.

Back in 2013, when I knew much less about autism, I wrote about the experimental use of insulin like growth factor 1 (IGF-1) in autism.  

It’s a Small World – IGF-1 and NNZ-2566 in Autism


It turned out that in autism the many different growth factors can be disturbed (too much, or too little) and this variation does indeed define some specific types of autism.  For example in Rett Syndrome there are very low levels of Nerve Growth Factor (NGF); low levels of NGF in some older people is the cause of their dementia.  In more common types of autism NGF is actually elevated.

IGF-1 is very well studied.

 

IGF-1 is a primary mediator of the effects of growth hormone (GH). 

Growth hormone is made in the anterior pituitary gland, 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, especially skeletal muscle, cartilage, bone, liver,kidney, nerves, skin, hematopoietic cell, and lungs. This would explain why adults abusing GH may end up needing hip and knee replacements.

Before getting into the science, IGF-1 has long been available as a drug to treat children with growth delays.  In the US this drug is being used on children with a type of autism called Phelan-McDermid Syndrome.

Now, regular readers will recall from my last post on intranasal insulin that it was in this very syndrome that there was a successful intranasal insulin.

So most likely without delving into the science at all it looks like IGF-1 and intranasal insulin are both options to treat the same dysfunction.

Using IGF-1


Using Intranasal Insulin

Intranasal insulin to improve developmental delay in children with 22q13 deletion syndrome: an exploratory clinical trial.



NNZ-2566

This is an Australian drug that is a modified version of IGF-1 (a so called analog).  They modified it so that it can be taken orally rather than by injection.  The developer has a very thorough presentation showing why they think it should be effective in autism.  

  




The Science

The first thing to note is that insulin and IGF-1 act as messengers.  Disruption in growth factor signaling can have serious consequences.

Insulin and IGF-1 both activate the same insulin receptor (IR).

Most people think that insulin is a just a hormone produced in their pancreas that regulates the amount of glucose (sugar) in their blood.  It does of course do that, but it actually does much more.



  




Insulin receptors are expressed all over the body including the brain.

Here is a relatively simple presentation explaining the role of insulin signaling in the brain:-





Now for the diehard scientists among you that have been reading about all those signaling pathways that lie behind autism, cancer and many other hard to treat conditions, look at the graphic below.

We know the importance of RAS.  Impaired RAS signaling underlies the RASopathies, one feature of which is cognitive loss (MR/ID), another is autism.

We also know the importance of Akt (PKB/protein kinase B) in some types of autism.  PTEN appears again.










So irrespective of an undoubtedly important effect on glucose and insulin resistance, we should expect activation of insulin receptors in the brain, in some types of autism, to have a further positive effect.

It would seem to be a potential therapy for RASopathies.

As is often the case, there are extreme dysfunctions of RAS and I suggest there are more mild dysfunctions.

I suggest that some people with autism and some cognitive dysfunction have a partial RASopathy.

Since autism contains both extremes of many dysfunctions, there will undoubtedly be types of autism that respond negatively, or not at all, to activation of insulin receptors in the brain.



Practicalities

Nobody likes injections and that is necessary to give IGF-1.

NNZ-2566 is an experimental autism drug and on past performance that means it will take decades to reach the market, if ever.

That leaves insulin which was sitting all along in your local pharmacy.

Intranasal insulin was once investigated for use in diabetics, but it did not work.  It is not absorbed into the blood stream.

This is of course the huge advantage for people with autism, since we only want to activate the insulin receptors in the brain.  If you are not diabetic why would you want to have any effects in the rest of the body?

Indeed there are known major side effects of injecting IGF-1 or GH (growth hormone) into adults.  All kinds of things start growing and this can lead to terrible results.

The fact that all the studies show that intranasal insulin does not enter the blood stream and so lower blood glucose levels, makes it a much better drug for autism than IGF-1 or indeed NNZ-2566.


Insulin

There are various types of insulin and the main difference is that some are modified to be longer acting.

The basic insulin is soluble or clear insulin, and nowadays is synthetic rather than derived from pigs.  Examples include Humulin Regular/R/S by Lilly.

The standard concentration is 100 IU/ml.

The trials in Alzheimer’s and other conditions varied in dosage but generally used about 20 to 40 IU per day.

This is not a trivial dose.  If injected, rather than inhaled, that dose would have a significant effect on lowering blood sugar and would be dangerous.

My antihistamine nasal spray gives a metered dose of 0.14 ml.

So without any dilution, if filled with off the shelf insulin it would dispense 14 IU per spray.

So no special high tech drugs, dilutants/diluents or dispensers appear to be necessary. Some trials do use fancy inhalers, like the one in the video at the end of this post.

To be prudent it might be wise to dilute the insulin so as to gradually increase the dose.  Maybe in some people the nasal membrane is more permeable than in others.  Some of the trials did this, but most did not.

A fridge is required, because insulin needs to be kept chilled.

I do wonder why nobody seems to be researching this in autism.  Silly point, as one insulin researcher commented on the earlier post; there is no big money to be made, hence no interest.



Insulin & Alzheimer’s

The reasons that intranasal insulin improves Alzheimer’s, and likely will Down Syndrome, may differ to those help in (some) autism.

Beta amyloid is key to Alzheimer’s (and early onset Alzheimer’s in Down Syndrome) but is not a known issue in autism.  Central insulin resistance is an issue in Alzheimer’s and might well be in autism.  

Perhaps people with mitochondrial dysfunction (an energy conversion dysfunction) might particularly benefit from increased glucose uptake in the brain.  It appears that mitochondrial dysfunction plays a role in insulin resistance. 

Role of Mitochondrial Dysfunction in Insulin Resistance

The activation of the RAS pathway might be highly beneficial to some people with autism.  

Here is a good film, which refers to the studies from previous posts and shows the effect on one man with Alzheimer's. 





 You also see their fancy inhaler device.








Friday, 17 January 2014

Increasing Good Behaviors and Reducing Bad Behaviors in Autism

This blog is all about clever chemicals that can make life better for people with autism, but for several years I have also been learning all about behavioral therapy to achieve the same goal.  So I thought I should look for any lessons that I might apply from my earlier endeavours.  




Two of the best books in my ABA collection, based on feedback from all of our Assistants/Therapists/Friends are the oldest, and indeed the lightest.  They are more than 30 years old, as you might imagine from the front cover, which is a big turn off for many parents.

They are great books, that tell you what you actually want to know: how to get rid of horrible behaviours and how to encourage nice ones.
Dr Foxx is still going strong and won the 2013 Award for Distinguished Professional Contributions to Applied Research from the American Psychological Association. Foxx is a professor of psychology at Pennsylvania State Harrisburg and an adjunct professor of pediatrics at the Pennsylvania State University College of Medicine.

The thing I always found odd was why Dr. Foxx wrote two separate books, surely it is all the same subject matter.  He had his reasons.
Here is my parallel with my quest to develop a smart combination of safe drugs to help in autism. 

So far, most of what I have been doing is focused on decreasing the bad behaviors, so the blue part of the pill; the remaining work is find to ways to promote the good behaviors, the yellow part of the pill.

This might actually be more relevant that you realize.  While it is clear that bad behaviors in autism vary widely in both type and extent, desirable good behaviors should have much more in common.  We know that many individual drugs on the "blue side" are effective only in a minority of people, but perhaps there will be much more commonality on the "yellow side".  I expect this to be the case.
So my Polypill is taking colour, as well as shape.

Another good piece of news is that I found a precedent for orphan drug designation in classic autism.  It appears that in 1998 the FDA awarded orphan drug status to Naltrexone to treat childhood autism with SIB.  In the US, orphan drug status is only possible for rare diseases affecting less than 200,000 people.  There are other cases of orphan drugs in autism, but they are for rare genetic variants. Currently the FDA website for orphan drugs does not list Autism for Naltrexone.
Also, an interesting Australian drug NNZ-2566,  mentioned in a previous post, has recently been given orphan drug status in the US, this time based on Fragile X designation.  The drug is an analogue of IGF-1 and looks interesting to me.

If you want to see what orphan drug designation in the EU means, here is what Novartis received for its new Fragile X treatment, Mavoglurant.
Orphan drug status reduces the cost of approving a drug.  But how rare is classic autism, these days?

 

Thursday, 5 December 2013

Autism Phenotypes

Hardly a week goes by without somebody mentioning to me a wonder treatment or even “cure” for autism; the latest one being the GAPS diet.

I think all such reports are worthy of investigation, but many lead to nowhere.

Why is this?




  
·       Medical science has failed to adequately define autism, so we are not all talking about the same autism

·        Many people putting forward theories have not read even the most basic (and not contested) autism research.  Some are even, apparently, qualified “doctors”.
 
Autism Phenotypes

What is not disputed is that autism has many sub-types (phenotypes). Researchers tell us 10-20% of cases referred to as autism have a known genetic defect (Fragile X, SLOS, Timothy syndrome etc.).  80% do not have a known genetic marker/cause.

Autism can be subdivided into regressive (when a child loses speech and other learnt skills) and non-regressive (early onset).  Even this can be a subjective judgment, since it effectively relies on parents to determine it, after the event.
Then you have cases of autism which clearly have nothing to do with Kanner’s classic version.  In this blog I showed how even cerebral malaria in a child can lead to the onset of autism.  This clearly is a case of brain damage caused by malaria; but to the observer, months later, it would probably be classed as regressive autism or childhood disintegrative disorder.
 
Testing for Autism
Researchers and doctors keep repeating that there is no test for autism.  This is not strictly true, but it does explain why so many different conditions are all lumped together as “autism”.

In fact, if you read the research closely, you will see that there are many tests for autism; although they may not be perfect.
The only way to know for sure that it is genuine autism is to examine the brain itself.  The only way to do this 100% accurately is via post-mortem analysis of the brain.  Recently, non-invasive methods have been developed to confirm the same findings of brain malformation that occurred prior to birth.

So the kind of autism that relates to tissue held in brain banks is best understood.  But what kind of autism would that be?  Well, it refers mainly to children and young adults who died prematurely.  They died from things like seizures or drowning.  What does that tell us?  This tells us that these people were most likely severely affected by autism.  The mild, social difficulties, type of autism is, fortunately, hardly likely to make it to the brain tissue bank.
If the person interpreting the MRI of a child’s brain knows what to look for, they may very well be able to identify this type of autism.  The expert here is Eric Courchesne.
A similar approach can followed using Electroencephalography (EEG) to identify autism; but it would be smart to cross check this with Eric.

Regressive vs. Early-Onset
Then you have the difference between regressive and non-regressive autism.  Here again, from my Dean’s List of researchers, we look at Paul Ashwood’s research to see that kids with regressive autism have HIGHER levels of inflammatory markers in their blood.  These include cytokines like interleukin 6, which can be inexpensively measured in most laboratories.  This tells us that perhaps regressive autism is an entirely different condition from non-regressive/early onset autism.  As I would expect, increasing cytokine levels were associated with more impaired communication and aberrant behaviors. 
 
Lab Testing
We have seen earlier in this blog that some very expensive lab tests exist for autism, but their usefulness and integrity is highly disputed.  There are, of course, many hundreds of other tests that are entirely validated by medical science.  Many of these tests are cheap and available all over the world.

Hormonal Screening
We know from the research that about 30% of people with autism have high blood serotonin. A standard lab test is required.
We know that many have high levels of insulin-like growth factor (IGF-1).  A standard lab test is required.
Thyroid hormone levels and in particular a blunted response of TSH to TRH (i.e. central hypothyroidism) can help define further phenotypes.

The TRH test is now not widely used, but TSH, FT3 and FT4 are cheap tests.
Growth Hormone (GH) is also implicated in autism, along with IGF-1; there is a lab test to measure pituitaryfunction to see how well GH is being produced.

By screening for hormonal dysfunction, it would be possible to identify phenotypes that would most likely benefit from therapies targeting those defects, like NNZ-25266.

Pancreatic Dysfunction
It is reported by Joan Fallon, of Curemark, that 50+% of kids diagnosed with “US autism” seem to have a pancreatic dysfunction.  This can be tested for by measuring fecal chymotrypsin level.  The test measures how well your pancreas is working, and is a standard test for people with cystic fibrosis.  Since the US diagnoses far more kids with autism than other countries, it seems highly plausible that “US autism” includes many more phenotypes than, say, “French autism”.

I was quoted about $8 for a chymotrypsin test.

Ion-Channel Diseases (Channelopathies)
Many diseases like Parkinson’s disease, Spinocerebellar Ataxia and Timothy Syndrome are caused by faulty calcium ion-channels.

The Bumetanide autism therapy, undergoing trials in Europe, is based on another channelopathy, this time a faulty chloride transporter NKCC1.
It is clear from reports I have received, that Bumetanide therapy is totally ineffective in some children with ASD, but in other children, like my son, it is effective.
So some types of autism have certain channelopathies and other types have different ones or, quite possibly, none at all.  


Conclusion
My conclusion today is pure conjecture.  I imagine that possibly as few as a quarter of cases of “US autism” are actually “real” autism, that is with all the brain damage/malformation that is identified in those post mortem brain studies and which forms the basis of 90% of autism research.

The other three quarters may be something entirely different, just like the case of the mosquito that bit the child, produced cerebral malaria and then later the full symptoms of autism.  Within the three quarters may be food allergies, digestive enzyme deficiencies, gut disorders, mastocytosis, blood brain barrier defects, undefined calcium ion-channel diseases etc.
This would account for those occasional amazing “recoveries” and the apparent success, in some cases, of diets like GAPS.  Sadly, diet is unlikely to 100% fix brain damage.  If you are lucky enough to totally “recover”, you cannot have had brain damage in the first place.  It is evident that in some phenotypes of autism, diet can reduce autistic behaviours.  This can only be proved in trials, if biomarkers are established for that specific phenotype.
Most likely the only biological thing all these “autisms” have in common is oxidative stress and neuroinflammation; but only a non-medical scientist, like me, can say such a thing.

 

 

Monday, 11 November 2013

Creatine, the Sub-types of Autism is Affects, and the Missing $26 million



Poly Genetic Theory of Autism

Autism appears to be the result of the expression of multiple abnormal genes acting in concert, likely initiated by some external factor(s).  This would explain why there are so many variants of autism and why there can seem to be autistic-like traits in close relatives.
 

 

Gene-based Autism Research
Several candidate genes have been identified, such as those linked to fragile X syndrome, tuberous sclerosis etc.  Researchers then follow the science from the target gene to identify a possible therapy.  At this point the researchers then seem to lose their scientific logic; they then try and apply their new therapy to all kinds of autism, i.e. the ones without the “faulty gene”.

This really goes back to our current limited understanding of the brain, medicine is more art than science, and we should perhaps suspend logic and accept this trial and error approach as valid.  At least call it trial and error.

Creatine
Creatine is an organic acid produced naturally in the body.  It helps to supply energy to all cells in the body. This is achieved by increasing the formation of adenosine triphosphate (ATP).

Creatine is not an essential nutrient, as it is manufactured in the human body from L-arginine, glycine and L-methionine.
Its main use as a supplement/drug is among people wanting to develop their muscles, like athletes and bodybuilders.  Taking the standard dose of 5-10 mg has the same effect as eating a very high protein diet.  In people with muscle wasting diseases, Creatine is also used.  What I found interesting was the research showing an effect in depression.  There are marked similarities between conditions like depression and ASD.
We will return later in the post to another reason that Creatine may be relevant to autism; it appears to be something the research community did not notice.  Now back to those professional researchers:-
 
Creatine Deficiency
Science has identified three types of Creatine deficiency and all three lead to mental retardation and/or autism.  Two types are very rare, but are treatable; the third type is far more common, affecting about a million people worldwide, and is currently untreatable in humans.  In mice, this third type has been “cured”, but the money is not yet available to develop and test a human version of the therapy.
 
 
1.      AGAT 
AGAT (L-Arginine:glycine amidinotransferase) is an enzyme.  This enzyme is needed for the body to produce Creatine.  AGAT deficiency will cause Creatine deficiency  and lead to mental retardation and autism.
For those regularly following my blog, please note the following: It has been suggested that AGAT activity in tissues is regulated in a number of ways including induction by growth hormone (GH) and thyroxine (T4).

The actual genetic mutation associated with AGAT involves a tryptophan codon being converted to a stop codon at residue 149.
You may recall in my post on serotonin, we learnt about its precursor tryptophan and how it appears to be degraded in the autistic brain.


2.     GAMT
GAMT (Guanidinoacetate N-methyltransferase) is another enzyme required to produce Creatine.  As with AGAT deficiency, if you are deficient in GAMT, autism and mental retardation will follow.

Treatment
If diagnosed, defects of Creatine biosynthesis are treated with Creatine supplements and, in GAMT deficiency, with ornithine and dietary restriction of arginine through limitation of protein intake.
 
3.     X-linked Creatine deficiency
The final type of Creatine deficiency is much more common, but is much more difficult to treat.  The defect is the Creatine transporter that should allow the Creatine into brain cells, where it plays a critical role in the brain’s energy needs.  No matter how much Creatine you give to people with this disorder, they cannot use it, because their Creatine transporters (CRTs) are defective.

Fortunately, thanks to Dr Joseph Clark, Professor of Neurology at the University of Cincinnati, there is light at the end of the tunnel.  Dr Clark has been researching the Creatine metabolism for some years.  Very unusually, he has been sharing his experiences with us, via his blog.
To cut a long story short, the good doctor has figured out that by using an analog (a modified version) of Creatine called cyclocreatine he could normalize the function of mice with  X-linked Creatine deficiency.  All he now has to do, is to make it work in humans, fully test it and get it FDA approved.  The problem is there is no more money.  In his blog post he tells us that all he needs is:-
$26 million and three more years

Here is the official report from the University:- 
 
Peter’s thoughts on Creatine
I started looking at Creatine because it appears to stimulate IGF-1 (insulin-like growth factor 1).  This is not a fact well-known to endocrinologists, but it is very well known to athletes and body builders.  They take Creatine orally and it stimulates muscle growth.  Research has even measured the change in IGF-1 in muscle tissue resulting from Creatine supplementation.

In a recent post I pointed out that IGF-1 is itself being used in autism trials, as is a novel Australian analog of IGF-1 [1-3] called NNZ-2566.  The big advantage of NNZ-2566 is that it is taken orally.

The release of IGF-1 is stimulated by growth hormone GH.  Secretion of growth hormone (GH) in the pituitary is regulated by the hypothalamus, which release the peptides Growth hormone-releasing hormone (GHRH) and Growth hormone-inhibiting hormone (GHIH) into the blood surrounding the pituitary. GH release in the pituitary is primarily determined by the balance of these two peptides, which in turn is affected by many physiological stimulators (e.g., exercise, nutrition, sleep) and inhibitors (e.g., free fatty acids) of GH secretion.
Stimulators of growth hormone (GH) secretion include:
  • peptide hormones
    • GHRH  through binding to the growth hormone-releasing hormone receptor
    • ghrelin through binding to growth hormone secretagogue receptors
  • sex hormones
    • increased androgen secretion during puberty (in males from testis and in females from adrenal cortex)
    • estrogen
  • clonidine and L-DOPA by stimulating GHRH release

·         α4β2 nicotinic agonists, including nicotine, which also act synergistically with clonidine 
      (Interestingly clonidine is a drug used for ADHD, or autism-lite, as I call it)

Factors that are known to cause variation in the levels of (GH) and IGF-1 in the circulation include: genetic make-up, the time of day, age, sex, exercise status, stress levels, nutrition level and body mass index (BMI), disease state, race, estrogen status and xenobiotic intake. The later inclusion of xenobiotic intake as a factor influencing GH-IGF status highlights the fact that the GH-IGF axis is a potential target for certain endocrine disrupting chemicals. These are chemicals found in both household and industrial products that are known to interfere with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body that are responsible for development, behavior, fertility, and maintenance of normal cell metabolism. 
Based on my earlier primary research, I am pretty sure that in the sub-type of autism I am dealing with, there is a deficiency of either GH or TRH, in the brain.  As I result, I am interested in mention of these hormones.


 SHANK3 deficiency
(also known as 22q13 Deletion Syndrome or Phelan-McDermid Syndrome)

IGF-1 is being trialled at Mount Sinai Hospital in New York in autistic children with SHANK3 deficiency.  In true “art” rather than “science” approach, the plan is then to trial IGF-1 on children without SHANK3 deficiency.

Here is a good explanation.
If you live in the Big Apple:-

Where Can I Get Testing?


The Icahn School of Medicine at Mount Sinai offers genetic testing for Phelan-McDermid Syndrome/22q13 Deletion Syndrome and for SHANK3 mutations. A blood sample is needed to conduct the test. For more information about testing, visit The Seaver Autism Center, call (212) 241-0961  

It appears that SHANK3 deficiency accounts for about 1% of autism cases.
If, as is hoped, IGF-1 turns out to be a useful therapy in SHANK3 deficient children, it will be tried on all ASD kids.  If it works, then what was the relevance of SHANK3 in the first place?   It seems pretty odd to me.  I think most likely our current understanding of genetics is so basic, as to be flawed.

I am working via observation, rather than genetics; I know what circumstances produce near neurotypical behaviour, I just need to understand what is going on biologically.  This is how I ended up with TRH and/or GH.


Conclusion
Well if the Mount Sinai study is successful, as it probably will be, we should find Dr Clark in Cincinnati and give him $26 million.  Then we put creatine and cyclocreatine in a pill and give it to ALL people with ASD, since 99% will never get their sub-type diagnosed. 

Either the creatine, the cyclocreatine or the extra IGF-1 will do some good, depending on the sub-type – something for everyone. And no needles.