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.
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.
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."
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.