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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.


 

2 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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