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Wednesday 30 October 2013

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


You may or may not believe in fate, but some strange things have been happening related to Australia, growth hormones and TBI.

Last week I took Monty, aged 10 with ASD, to have his IGF-1 (insulin-like growth factor) measured.  At the time, this had nothing to do with autism, rather just what the Endocrinologist had requested.  Then I start doing my research on hormones and autism and found, surprisingly, there is an ongoing clinical trial in autism using IGF-1.  Then I start looking again at TBI (Traumatic Brain Injury), which I see as having much in common with ASD.  I looked for similarities in hormone disruptions found in TBI and ASD; I found there are many and they are mainly related to GH (growth hormone) and IGF-1.  The problem with IGF-1 therapy is that it is intravenous; I had told the Endocrinologist that I was not going to measure IGF-1, because I was not very keen on giving Monty intravenous drugs.  In the end, I did the test anyway and I am glad I did.
As I researched TBI, I saw a great deal of interest in using GH as a therapy and the US military is providing a great deal of funding to develop therapies.

Today the postman brings me my first post from Australia in several years.  It contains some children books for Monty (Thank you Lisa).
Now I come across NNZ-2566;  it is a synthetic analogue of a naturally occurring neurotropic peptide derived from IGF-1.   NNZ-2566 is being developed both in intravenous and oral formulations for a range of acute and chronic conditions including TBI, Fragile X and Retts syndrome.  NNZ-2566 exhibits a wide range of important effects including inhibiting neuroinflammation, normalizing the role of microglia and correcting deficits in synaptic function.  NNZ-2566 is being developed guess where? Australia, by Neuren Pharmaceuticals.

Just 10 days ago the company made the following announcement:-
Melbourne, Australia, 18 October 2013: Neuren Pharmaceuticals (ASX: NEU) announced today that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for Neuren’s programme to develop NNZ-2566 for Fragile X Syndrome. Fast Track designation is designed to expedite the development and review of important new medicines that are intended to treat serious diseases and meet unmet medical needs.
A different group of researchers are poised to begin clinical trials of IGF-1 in children with autism early next year. Because IGF-1 is already approved in the United States for use in children with short stature, the U.S. Food and Drug Administration is allowing the researchers to proceed directly to clinical trials for its use as an autism treatment.
What a lot of coincidences.
For those scientists among you, here are more details.

First of all it has been shown that in autism there are elevated levels of growth hormones.  Here is an American study.

 The Australians quote research from Finland that looks to me to contradict the above paper.  One difference is that the US researchers were testing blood and the Finns were testing spinal fluid.  What is clear is that in autism IGF-1 is not normal.

Abstract
Rett syndrome is characterized by disruption of a period of vigorous brain growth with synapse development. Neurotrophic factors are important regulators of neuronal growth, differentiation, and survival during early brain development. The aims of this study were to study the role of neurotrophic factors in Rett syndrome, specifically whether Rett syndrome has abnormal levels of specific neurotrophic factors in serum and cerebrospinal fluid and whether the changes differ from other neuropediatric patients, for example, those with infantile autism. Four neurotrophic factors were measured: nerve growth factor, brain-derived neurotrophic factor, glial cell line—derived neurotrophic factor, and insulin-like growth factor 1 from the frozen cerebrospinal fluid and from serum (except glial cell line—derived neurotrophic factor) by enzyme-linked immunosorbent assay and cerebrospinal fluid glutamate and aspartate by high-performance liquid chromatography (HPLC) method in patients with Rett syndrome. Insulin-like growth factor 1 was measured from the cerebrospinal fluid of patients with infantile autism. We found low concentrations of cerebrospinal fluid nerve growth factor in patients with Rett syndrome compared with control patients. The serum levels and other cerebrospinal fluid neurotrophic factor levels of the patients did not differ from the controls. Patients with Rett syndrome had high cerebrospinal fluid glutamate levels. Patients with infantile autism had low cerebrospinal fluid insulin-like growth factor 1 levels. Nerve growth factor acts especially on cholinergic neurons of the basal forebrain, whereas insulin-like growth factor 1 acts on cerebellar neurons. In Rett syndrome, the forebrain is more severely affected than the other cortical areas. In autism, many studies show hippocampal or cerebellar pathology. Our findings are in agreement with the different morphologic and neurochemical findings (brain growth, affected brain areas, neurotransmitter metabolism) in the two syndromes. Impairment in dendritic development in Rett syndrome could be the consequence of cholinergic deficiency and of neurotrophic factor/glutamate imbalance. Cholinergic gene expression might be influenced by the Rett syndrome gene directly or via the neurotrophic factor system.
 Then we have research showing GH/IGF-1 has secondary functions beyond those in the text books.  Lots of nice words like neuroprotective, regenerative etc.

Abstract

The growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis is not only involved in brain growth, development and myelination, but also in brain plasticity as indexed by neurogenesis. This may have links to various cognitive effects of GH and IGF-1. GH and IGF-1 affect the genesis of neurons, astrocytes, endothelial cells and oligodendrocytes. Specifically, IGF-1 increases progenitor cell proliferation and numbers of new neurons, oligodendrocytes, and blood vessels in the dentate gyrus of the hippocampus. In the adult cerebral cortex IGF-1 only affects oligodendrogenesis. Recently, GH therapy has also been shown to induce cell genesis in the adult brain. The profile of effects by GH therapy may be somewhat different than that of IGF-1. In addition, GH secretagogues (GHS) also have neuroprotective and cell regenerative effects per se in the brain. Finally, transgenic disruptions in GH signaling pathways affect neuron and astrocyte cell numbers during development and during adulthood. Altogether, data suggest that both exogenous and endogenous GH and/or IGF-1 may be used as agents to enhance cell genesis and neurogenesis in the adult brain. Theoretically these substances could be used to enhance recovery after brain injuries. However, further experiments with specific animal models for brain injuries are needed before clinical trials can be started. 
For those of you that like mice studies:
Now back down under to let the Aussies make their case:

The Case for IGF-1 and IGF-1 (1-3) Glypromate in Autism
Courtesy of our friends “down under” you can read a presentation explaining the likely merits of both IGF-1 and its “terminal tripeptide” IGF-1 (1-3) as therapeutic agents in autism.  The clever Aussies have gone one better and produced NNZ-2566.  It is an analog of and IGF-1 (1-3).  This means it has that the molecule has been very slightly modified.  In this case this has been done to allow it to be orally available (i.e. not by injection) and to better cross the blood brain barrier (BBB). 

Mount Sinai Hospital Clinical trial of IGF-1
Mount Sinai Hospital is a leading US teaching hospital in New York; they are carrying out a trial of IGF-1 in autism.  They are starting with a sub type with a genetic deficiency called SHANK3, but they will then look at the benefit in other types of ASD. 

"In an important test of one of the first drugs to target core symptoms of autism, researchers at Mount Sinai School of Medicine are undertaking a pilot clinical trial to evaluate insulin-like growth factor (IGF-1) in children who have SHANK3 deficiency (also known as 22q13 Deletion Syndrome or Phelan-McDermid Syndrome), a known cause of autism spectrum disorder (ASD).
The seven-month study, which begins this month, will be conducted under the leadership of the Seaver Autism Center Clinical Director Alex Kolevzon, MD, and will utilize a double-blind, placebo-controlled crossover design in children ages 5 to 17 years old with SHANK3 deletions or mutations. Patients will receive three months of treatment with active medication or placebo, separated by a four-week washout period. Future trials are planned to explore the utility of IGF-1 in ASD without SHANK3 deficiency."

 
Conclusion

For a change, my conclusion is that further study is needed (by me).  Probably all the hormonal disruptions in autism need to be looked at together (serotonin, T3 etc) before any wild conclusions are drawn.


 

20 comments:

  1. Thank you for this post. NNZ-2566 is very interesting, although there's a lot of sales hype in the information surrounding it. I find it fascinating that at their web page, they mention how both Rett and Fragile X dendritic abnormalities are corrected in mouse models. There's also a paper out that details this, and talk about involvement of GABA-B, glutamate, akt and mtor, etc. This brings me to another topic: I'm about to try a compound on myself that orally can produce increased IGF levels. It's called MK-677 (Ibutamoren), and can be acquired by reputable (and not so reputable) peptide vendors. It's not something I would consider for a kid, though. I'll let you know how it goes. I had my IGF-1 levels tested, and they were in the 1-2 percentile of my age group. May I ask what Monty had? These peptide vendors have some other substances currently lacking patents that are worth discussing in a post, such as tianeptine and selank and newer racetams. AFAIK, no one has tested them yet in an ASD context. /Joel

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    1. Hi Joel, my son had 305 ng/ml of IGF-1. This is within the reference range for his age at that time (70-458), but was seen as high. So no need to add GH or IGF-1.

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  2. This is very interesting, thanks for the information. Since then, any news about this? It seems very interesting.

    The hormone imbalance of autist kids should be checked and treated.

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  3. IGF-1 and GH levels in Rett are normal, what's overexpressed at up to 4 folds is IGFBP3. This is a consecuence of the MECP2 gene supression failure an it implies a lack of IGF-1 bioavilty. What Neuren is developing are synthetic analogues of natural peptides that compite with IGFBP3 to bind IGF-1 with the right receptors. https://academic.oup.com/jnen/article/66/2/117/2916759?login=false
    cGP is and end product and is seems to be fairly estable. It has a reversible homeostatic role. It could also help reducing the excess of IGF-1 activation of some autism variations in the same way it also reduce tumors: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955921/
    You can get a source of natural cGP here: https://cgpmax.com/
    It seems to be working with my 3 years old Rett lady.

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    1. Nerve Growth Factor (NGF) has been shown to be reduced in Rett. Also, interestingly KCC2 is underexpressed, that would lead to same E/I imbalance found in bumetanide-responsive autism.

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  4. My daughter has elevated blood creatinine levels. Just one year ago the metabolic disorders doctor suspected a creatine deficiency disorder, and the paediatrician suspected a possible kidney dysfunction, so KCC2 aside Bumetadine could even be beneficial for her but I need to convince a doctor. The fact that it’s hard for her to drink is making me think twice.

    It seems that Neuren is succeeding with the Rett extended trial. So I expect to start soon a treatment combining GH and cGP. Monday I am visiting a Doctor who's published great results combining IGF-1 and cGP: https://minerva.usc.es/xmlui/handle/10347/23882

    In a few months Anavex extended trial will post results. Then I will decide if I also should add Afobazole.

    Hopefully IGF-1 and cGP will facilitate my daughter to swallow more water, then I will check with my doctor if it's possible to get Bumetanide prescribed.

    So far we’ve treated her with suplements like CDP choline, NaturDAO, Ubiquinol, Lion’s male, Resveratrol… we’ve seen a positive and significant improvement.

    Resveratrol overexpresses KCC2 in Rett mouse and organoid models. We are supplementing her with the equivalent of 18 adult glasses of red wine. Anyone looking to supplement Resveratrol should look for a clean purple colour as a quality sign.

    She’s completely calmed, connected, focused and no longer irritated since we started supplementing specifically for Rett. Is it supplements or Rett natural evolution? I do not know, but all Rett girls I’ve seen are much more affected than her. She seems to be getting better and better which is a completely opposite experience than watching her regressing or getting worse and worse.

    The potential of cGP to help improving any neurological condition should not sub-estimated: two daily pills of blackcurrant extract in a 30 days course elevated 70% the CSF cGP level in older people. Convert the same dose to the weight of a kid and you might get a highly significant increase of bioavailable IGF-1.

    Neuren is succeeding with cGP on a diverse range of animal models disorders: Angelman, Pitt Hopkins, Phelan- McDermid.. I think they are not going for autism due to the lack of genetic diagnosis but I would definitely give a try due to it’s antinflamatory and IGF-1 homestatic role.

    I suggest reading Neuren annual reports keeping in mind that in 2018 it was discovered that cGP was naturally found in blackcurrants.

    Yes, I haven’t bought any Neuren or Acadia shares, there are better opportunities in the market.

    Thank you for your blog Peter! I am aware of the great success your child had with Bumetadine and this inspires me to look for the same with my daughter.

    If I hadn't read your blog and the ones from others it would have been much harder when I got the hopeless Rett diagnosis from the doctor. It seems they gave it to me in a way they wanted me to surrender as soon as possible to their reality. Instead of I put the doctor quickly into trouble when I asked her for specific details on Trofinetide and Anavex trials

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    1. You could ask this doctor about an HDAC1 inhibitor. HDAC1 is a top 5 interacting protein with the Rett gene.

      Valproic Acid which is among other things an HDAC1 inhibitor was beneficial in the mouse model of Rett syndrome. It is cheap and widely used in epilepsy in children.

      HDAC1 affects the expression on very many genes.

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  5. Thank you Peter!

    After reading your advice I made some research.

    You were right, HDAC inhibitors are a promising target in Rett. What I also found was that valproic acid was already trialled in humans as an HDAC inhibitor but the doses that were considered safe were too low to replicate animal models' results. So I need a doctor who knows very well valproic acid and would feel comfortable prescribing it a large doses

    Anyway, melatonin is also an HDAC inhibitor. Melatonin at therapeutic doses is also considered a very potent mitochondrial anti-oxidant. The doctor prescribed us therapeutic melatonin. In adults that could be around 600mg. I wouldn’t be surprised if a significant chunk of the success with the Rett treatment would be thanks to the Melationine HDAC inhibitor effect.

    So, a therapeutic dose of melatonin could deliver a 2x1 effect.

    So far, this is what a Rett polypill could look like;
    1. IGF-1 + cPG (dendrites growth and plasticity)
    2. Melatonin (ROS + HDAC inhibition)
    3. Afobazole (Sigmar-1 chaperones)
    4. Bumetadine (Gaba modulation)

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  6. I found that terpeutic dosis of melatonin can significantly increase KCC2 and BDNF levels after traumatic brain injury: https://sci-hub.hkvisa.net/10.1111/jpi.12344

    I was wondering if it might have a similar effect on epigenetically downregultaed KCC2

    What do you think Peter?

    I think I know your answer, try and see?

    Thank you!
    Daniel

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    1. Daniel, I often do look at what is beneficial in TBI (traumatic brain injury) on the basis that it may moderate autism. Melatonin is a potent antioxidant and anti-inflammatory. It looks good for mitochondrial disorders..

      Will it upregulate KCC2 in people without TBI? It might do.

      The only drawback is melatonin"s effect on sleep. This will limit high doses to near bedtime.

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    2. Daniel, your information about Melatonin is very striking. They've used a very high dose of 10mg/kg in that paper. Do you have any personal experience to share? Did you give that high a dose?

      Peter, I'm a newbie here. So thankful that I found your blog. I'm in the world of biomedical treatment for about 2 years now and so surprised it took this long to get to your blog. Only after searching Bumetanide and carefully reading every single comment I was able to find this amazing blog. The information and science you post are way ahead of what I can find in other support groups. Hats off to you.

      I'm a mom of 3.10 yr old boy with severe regressive non-verbal Autism

      -Janu

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    3. Hi Janu!

      I myself tried similar high doses of melatonin for a few days and it was fine. It was not a big deal to wake up in time as usual and I found no significant added sleepiness in the office.

      I then tried for 3 days with my daughter but at that time my daughter was also taking cGP and somehow I found them to be incompatible. When cGP accumulates in the brain it’s quite exciting (alertness). During those 3 days, my daughter seemed to get more irritable willing to sleep but not able to do so.

      I discontinued and concluded that high doses of melatonin might be very useful for those whose circadian rhythms had already been compromised like older Rett girls. This is not yet the case with our daughter.

      The alertness induced by cGP helped me see clearly that of all the possible Rett treatments I should prioritise the Gaba shift and I focused my attention on Bumetanide.

      I definitely will go back to melatonin for myself and my daughter in the future but by then I will probably test our melatonin production before supplementing.

      Here is a Spanish research centre for melatonin: https://institutodemelatonina.com/

      They might help testing your son’s melatonin capacity.

      I hope this helps!

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  7. Peter, I would like to try the low dose of LDN for Denis, NAG didn't work and I see that Galavit with hydroxyzine doesn't kiss it overstimulates it, we're ok on verapamil, atarax, but we need something else to go on vacation for a few days, do you think it's worth it a low dose LDN test ???

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    1. Low dose Naltrexone is definitely worth a try. Others readers of this blog report a benefit.

      Did you ever try Pioglitazone? This is my summertime add on therapy.

      Delete
  8. 3 months after supplementing two capsules a day of cGPMAX (NNZ-2599) to my 44 months Rett daughter. This is what we've felt:
    There's been an increase in awareness and more remarkably an increase of purpose. Gross and fine motor skills have improved.
    There has also been a build up of anxious-like behaviour. After three months our daughter looked exhausted from too much alertness and anxiety.
    We discontinued cGP and in a couple of days the anxiety/alertness was gone.
    What we see now is like another girl, much more calmed and conscious than before starting with cGP.
    Was all of this a cGP effect? After reading all science, it looks that IGF1 activation in the CNS increases NAK Atp affecting action potentials. It also stimulates KCC2 development. So maybe cGP was behind these positive changes and we will return to two or one capsule a day and will simply reajust to avoid excessive estimulation.

    Below some related papers:

    Early IGF-1 primes visual cortex maturation and accelerates developmental switch between NKCC1 and KCC2 chloride transporters in enriched animals
    https://pubmed.ncbi.nlm.nih.gov/26924708/

    IGF-1 facilitates extinction of conditioned fear
    https://elifesciences.org/articles/67267

    Effects of insulin-like growth factor 1 on synaptic excitability in cultured rat hippocampal neuron
    https://sci-hub.hkvisa.net/10.1016/j.expneurol.2007.01.029

    Insulin-Like Growth Factor-1 Down-Regulates the Phosphorylation of FXYD1 and Rescues Behavioral Deficits in a Mouse Model of Rett Syndrome
    https://www.frontiersin.org/articles/10.3389/fnins.2020.00020/full

    Correcting deregulated Fxyd1 expression rescues deficits in neuronal arborization and potassium homeostasis in MeCP2 deficient male mice
    https://pubmed.ncbi.nlm.nih.gov/29902467/

    Accordingly, a decrease of Na(+), K(+)-ATPase increases neuronal excitability and may predispose to appearing of seizure activity
    https://pubmed.ncbi.nlm.nih.gov/25907445/

    Na,K-ATPase signal transduction triggers CREB activation and dendritic growth
    https://www.pnas.org/doi/10.1073/pnas.0809253106

    The sodium-potassium pump is an information processing element in brain computation
    https://www.frontiersin.org/articles/10.3389/fphys.2014.00472/full

    FXYD1 is an MeCP2 target gene overexpressed in the brains of Rett syndrome patients and Mecp2-null mice | Human Molecular Genetics
    https://academic.oup.com/hmg/article/16/6/640/611806

    FXYD proteins: new regulators of Na-K-ATPase
    https://journals.physiology.org/doi/full/10.1152/ajprenal.00126.2005

    FXYD1, a modulator of Na+,K+-ATPase activity, facilitates female sexual development by maintaining GnRH neuronal excitability
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2934895/

    FXYD proteins and sodium pump regulatory mechanisms
    https://pubmed.ncbi.nlm.nih.gov/33688925/

    FXYD6 Is a Novel Regulator of Na,K-ATPase Expressed in the Inner Ear
    https://www.sciencedirect.com/science/article/pii/S0021925820635876

    FXYD Proteins: New Tissue‐ and Isoform‐Specific Regulators of Na,K‐ATPase
    https://nyaspubs.onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.2003.tb07219.x

    FXYD7 is a brain‐specific regulator of Na,K‐ATPase α1–β isozymes
    https://www.embopress.org/doi/full/10.1093/emboj/cdf330

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    1. Daniel, good work.

      IGF-1 and NGF are very interesting and specifically for your daughter.

      I like the fact that your product is made from anthocyanins, the pigment from fruit/berries/vegetables. In your case it is blackcurrants. These are really interesting substances. I consume the betanin anthocyanin for its health properties (it is in beet root).

      I will write a post about cGP. It is another product for protecting against dementia/mild cognitive impairment (MCI) that will help some children.

      Delete
    2. Hi Peter!

      I shared the cGP papers with our functional doctor. He prescribed cGP to autistic children. In about 8 weeks He told me that some children had experienced an increase in phobias, tics and in one case convulsions appeared.

      This was not strange to me as I have also seen something similar with my daughter.

      All papers around Rett, cGP, IGF1, FXYD,... seem to match with what I felt, and the doctor’s experience confirms cGP might be potent and have an impact on certain kids.

      It might be interesting to spend some time looking into Neuren’s annual reports in a chronological way while bearing in mind that cGP and NNZ-2591 are mostly the same molecules: https://www.annualreports.com/Company/neuren-pharmaceuticals

      You should find cGP in all red fruits with anthocyanins, from cherries to beetroot. But we definitely will stay with cGPMAX for the convenience and reliability offered by the company.

      As far as I found cGP has a similar particle weight to sugar and is significantly lower than anthocyanins. For what cGPMAX confirmed to me their product is low in anthocyanins and rich in cGP. They probably have developed a specific extraction process to separate anthocyanins from cGP.

      I am working with our doctor to evaluate Bumetanide for my daughter. I found Bunmetanide should have no effect on non-mutated neurons and the impact on the overall Rett’s neurological excessive synchrony can be huge.

      Thank you for your blog. I have zero science background and would never have come to this without your inspiration.

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    3. Today Carla came back to Social Services therapy. These are carried by government staff and they tend to be very strict in their evaluations avoiding giving any unjustified hopes to parents as part of their role is to redirect kids into the right school curriculum and to put parents on the ground as soon as possible.

      The therapist is not aware of any treatment from our side. The last time She saw our daughter was 10 weeks ago. She observed:

      1- Carla has grown a lot. I agree with her because all suddenly it’s getting very hard to hold her in my arms. She is now taller but It also feels like She has stranger bonds and muscles.

      2- She was surprised to see another girl. Our daughter is now paying much more attention, She also communicates what She wants.

      For us, It’s a boost of confidence on cGP and we will get back to another round of treatment probably beginning next week. Half a pill in the morning and half a pill at night. I am getting to believe that cGP is potent and can stimulate too much.

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