Leukemia, IL-6 IL-10 and an Autism Flare-up

   

Leukemia/Leukaemia  is cancer that begins in the bone marrow and result in high numbers of abnormal white blood cells.

I received a comment on this blog a long time ago from a parent whose child had initially responded well to some of the autism therapies suggested on this blog. Later on all the therapies stopped working.  That child also has leukemia.

We now know this is a common event when you start treating autism, some comorbidity arises that blocks the effects of those therapies.  In my son’s case it is a simple pollen allergy, but it can be all kinds of inflammatory conditions such as colitis, IBS, IBD, GERD, celiac disease, juvenile arthritis, mastocytosis etc.  This list goes on, but now I know why it includes leukemia.

I do not consider epilepsy, or indeed cognitive dysfunction, as comorbidities.  Epilepsy is periodic extreme neuronal hyper-excitability, whereas in much autism there is chronic neuronal hyper-excitability.  Not surprisingly, chronic neuronal hyper-excitability can develop to periodic extreme neuronal hyper-excitability.  So I see epilepsy as a natural progression from childhood autism, but one that perhaps could and should be prevented.

Earlier on writing this blog I thought that genetics and cancer pathways would be beyond its scope, but in apparent absence of anyone much else publicizing the connections with autism I revised my view.

It has been known since 1930 that leukemia is comorbid with Down Syndrome (DS).  DS is caused by caused by the presence of all, or part of a third copy of chromosome 21 this leads to over expression of 300+ genes.  DS is usually easy to diagnose based on physical appearance .  The gene over-expression frequently leads to autistic behaviors and somewhat less frequently to various types of leukemia and in later years early onset Alzheimer’s.  The good news is that DS  children with acute myeloid leukemia (AML), and in particular the acute megakaryocytic leukemia (AMkL) subtype, have exceptionally high cure rates.

The particular gene that is over-expressed in DS and can cause leukemia is called HMGN1.

DS is increasingly rare in Europe, but quite common in the US due to differences in parental choice regarding the termination of pregnancies identified as high risk of Down Syndrome.

I think it only fair to consider leukemia as a possible comorbidity of autism, since may people with DS do indeed exhibit autistic behaviors.

There is no quality data to say how common leukemia is in non-DS autism.

 

Leukemia and Cytokines IL-6 and IL-10

I do consider the pro-inflammatory cytokine IL-6 to be public enemy number one of autism, while the anti-inflammatory cytokine is a potential friend.

There are different types of Leukemia, but it appears that IL-6 and IL-10 play a key role and at least in acute myeloid leukemia can predict the outcome.  Generally speaking leukemia is associated with elevated IL-6 and in particular when there is a relapse.

Acute myeloid leukemia (AML) blast cells frequently produce interleukin-6 (IL-6) 

“Serum levels of Interleukin-6 can be used as prognostic serum markers at diagnosis of adults acute myeloid leukemia and it could be used as follow up parameters for early detection of relapse stage”

Cytokine profiles in acute myeloid leukemia patients at diagnosis: survival is inversely correlated with IL-6 and directly correlated with IL-10 levels

An aberrant production of the pro-inflammatory cytokines IL-6 and TNF-α and the anti-inflammatory cytokine IL-10 is observed in AML patients. Low levels of IL-6 and high levels of IL-10 represent favorable prognostic factors for survival in AML patients. These results support the idea that cytokine deregulation may be useful as a marker for predicting clinical evolution in AML patients.

So we can infer that a leukemia relapse will likely lead to a worsening of autism driven by an elevation in the level of the pro-inflammatory cytokine IL-6.  This would account for why the autism drugs “stopped working” in the case of our reader.

We could then ponder that a therapy that reduces IL-6 and increases IL-10 might help keep some types of leukemia in remission.

This is altering the Th1/Th2 balance which was the target of our reader Alli from Switzerland who did decide to spend many hours reading the oncology research to understand all those cellular signaling pathways.

For those interested in why DS increases the risk of leukemia, scientists at the Dana-Farber Institute in Boston have figured this out, at least in the case of one common form of Leukemia.

Link between Down syndrome, leukemia uncovered

If only some more of the clever people studied autism.

Treating KCC2 Down-Regulation in Autism, Rett/Down Syndromes, Epilepsy and Neuronal Trauma ?

In this composite image, a human nerve cell derived from a patient with Rett syndrome shows significantly decreased levels of KCC2 compared to a control cell.  This will be equally true of about 50% people with classic autism, people with Down syndrome, many with TBI and many with epilepsy

In a recent post I highlighted an idea from the epilepsy research to treat a common phenomenon also found in much classic autism.  Neurons are in an immature state with too much intracellular chloride, the transporter that brings it in, called NKCC1, is over-expressed and the one that takes it out, KCC2, is under-expressed.  The net result is high levels of intracellular chloride and this leaves the brain in an over-excited state (GABA working in reverse) reducing cognitive function and with a reduced threshold to seizures.

The epilepsy research noted that increased BDNF is one factor that down regulates KCC2, which would have taken chloride out of the cells.  So it was suggested to block BDNF, or something closely related called trkB.

Unfortunately there is no easy way to this.  But I did some more digging and found various other ways to upregulate KCC2.

There is indeed a clever safe way that may achieve this and it is a therapy that I have already suggested for other reasons, intranasal insulin.

BDNF is a neurotrophin and other neurothrophins also have the ability to regulate KCC2. IGF-1 is another such neurotrophin and we even have very recent experimental data showing its effect on KCC2.

Regular readers will know that several trials with IGF-1, or analogs thereof, are underway.

I actually am rather biased against IGF-1 as a therapy, since in my son’s case the level of IGF-1 in blood is already high.  So I do not want to inject him with IGF-1 or even give him an oral analog.

However by using intranasal insulin the effect would be just within the CNS and insulin binds at the same receptors as IGF-1. So if IGF-1 upregulates KCC2 so will insulin.

We know from extensive existing trial data and direct feedback from one researcher that intranasal insulin is well tolerated and has no effect outside the CNS.

So rather to my surprise there seems to be a safe, cheap way to treat KCC2 down-regulation and this would also be applicable in epilepsy, traumatic brain injury (TBI) and any other condition involving immature neurons or neuronal trauma. 

The Science

There is a very thorough recent review paper that looks at all the ways that KCC2 expression is regulated.

Current view on the functional regulation of the neuronal K⁺-Cl⁻ cotransporter KCC2

The epilepsy researchers consider trkB, top left in the figure below.  But just next to it is IGFR which can be activated by both insulin and IGF-1.

In Rett syndrome they are already using IGF-1 to modulate KCC2.  The research is done at Penn State.

As you can see in the figure the mechanism for IGF-1 and insulin is not the same as BNDF/trkb, but Penn State have already shown that IGF-1 works in vitro.

We saw in early posts regarding intranasal insulin that this was a safe way to deliver insulin to the brain without effects in the rest of the body.

So we know it is safe and in theory it should achieve the same thing that the Penn State researchers are trying to achieve.

Signaling pathways controlling KCC2 function. The regulation of KCC2 activity is mediated by many proteins including kinases and phosphatases. It affects either the steady state protein expression at the plasma membrane or the KCC2 protein recycling. All the different pathways are explained and discussed in the main text. The schematic drawings of KCC2 as well as other membrane molecules do not reflect their oligomeric structure. GRFα2, GDNF family receptor α2; BDNF, Brain-derived neurotrophic factor; TrKB, Tropomyosin receptor kinase B; Insulin, Insulin-like growth factor 1 (IGF-1); IGFR, Insulin-like growth factor 1 receptor; mGluR1, Group I metabotropic glutamate receptor; 5-HT-2A, 5-hydroxytryptamine (5-HT) type 2A receptor; mAChR, Muscarinic acetylcholine receptor; NMDAR, N-methyl-D-aspartate receptor; mZnR, Metabotropic zinc-sensing receptor (mZnR); GPR39, G-protein-coupled receptor (GPR39); ERK-1,2, Extracellular signal-regulated kinases 1, 2; PKC, Protein kinase C; Src-TK, cytosolic Scr tyrosine kinase; WNKs1–4, with-no-lysine [K] kinase 1–4; SPAK, Ste20p-related proline/alanine-rich kinase; OSR1, oxidative stress-responsive kinase -1; Tph, Tyrosine phosphatase; PP1, protein phosphatase 1; Egr4, Early growth response transcription factor 4; USF 1/2, Upstream stimulating factor 1, 2.

The Penn State research on using IGF-1 to increase KCC2 in Rett Syndrome

Discovery of a new drug target could lead to novel treatment for severe autism

The researchers also showed that treating diseased nerve cells with insulin-like growth factor 1 (IGF1) elevated the level of KCC2 and corrected the function of the GABA neurotransmitter. IGF1 is a molecule that has been shown to alleviate symptoms in a mouse model of Rett Syndrome and is the subject of an ongoing phase-2 clinical trial for the treatment of the disease in humans.

"The finding that IGF1 can rescue the impaired KCC2 level in Rett neurons is important not only because it provides an explanation for the action of IGF1," said Xin Tang, a graduate student in Chen's Lab and the first-listed author of the paper, "but also because it opens the possibility of finding more small molecules that can act on KCC2 to treat Rett syndrome and other autism spectrum disorders."

More Melatonin?

As Agnieszka pointed out in the previous post it appears that extremely high doses of melatonin can increase KCC2 in traumatic brain injury (TBI). In this example BDNF was increased by the therapy, so I think TBI may be a specific case.  In most autism BDNF starts out elevated and in epilepsy, seizures are known to increase BDNF and that process is seen as down regulating KCC2 expression.  So in much autism and epilepsy you want less BDNF.

Melatonin attenuates neuronal apoptosis through up-regulation of K+ -Cl- cotransporter KCC2 expression following traumatic brain injury in rats

Compared with the vehicle group, melatonin treatment altered the down-regulation of KCC2 expression in both mRNA and protein levels after TBI. Also, melatonin treatment increased the protein levels of brain-derived neurotrophic factor (BDNF) and phosphorylated extracellular signal-regulated kinase (p-ERK). Simultaneously, melatonin administration ameliorated cortical neuronal apoptosis, reduced brain edema, and attenuated neurological deficits after TBI. In conclusion, our findings suggested that melatonin restores KCC2 expression, inhibits neuronal apoptosis and attenuates secondary brain injury after TBI, partially through activation of BDNF/ERK pathway.

More Science

There is plenty more science on this subject.

It is suggested that in addition to IGF-1/insulin it may be necessary to involve Protein tyrosine kinase (PTK).

Insulin-Like Growth Factor 1 and a Cytosolic Tyrosine Kinase Activate Chloride Outward Transport during Maturation of Hippocampal Neurons

Protein tyrosine kinase (PTK) phosphorylation is considered a key biochemical event in numerous cellular processes, including proliferation, growth, and differentiation, and has also been implicated in synaptogenesis. Protein tyrosine kinases are subdivided into the cytosolic nonreceptor family and the transmembrane growth factor receptor family, which includes receptors for insulin and insulin-like growth factor (IGF-1). The maturation of postsynaptic inhibition may require both a cytoplasmic PTK, which increases GABA_A receptor-mediated currents, and insulin, which was shown to induce a rapid translocation of GABA_A receptors from intracellular compartments to the plasma membrane. KCC2 is also known to have a C-terminal PTK consensus site. Therefore, the maturation of postsynaptic inhibition may, in addition to other mechanisms, also involve the effects of PTK and insulin acting on KCC2.

Development and regulation of chloride homeostasis in the central nervous system

Conclusion

I would infer from all this science that intranasal insulin is likely to increase KCC2 expression in the brain, certainly worthy of investigation.

Protein tyrosine kinase (PTK) phosphorylation is considered a key biochemical event in numerous cellular processes.  This might be a limiting factor on the effectiveness of insulin in raising KCC2.  This would then add yet more complexity.

Protein kinases are enzymes that add a phosphate(PO₄) group to a protein, and can modulate its function.  A protein kinase inhibitor is a type of enzyme inhibitor that blocks the action of one or more protein kinases.

Abnormal protein tyrosine kinases (PTKs) cause many human leukaemias, so there is research into PTK inhibitors (PTK-Is).

As we know from Abha Chauhan’s mammoth book, oxidative stress controls the activities of PTK.

Intranasal Insulin for Improved Mood and Cognition

  

This post follows on the previous one that raised the issue of brain-specific insulin sensitivity being a common feature of neurological diseases/disorders.

It appears to be much more than just a rare possibility.   There have been numerous studies and even more are ongoing.

Intranasal insulin has even been tried one single-gene type of autism (Phelan-McDermid Syndrome) and in autism’s big brothers, bipolar and schizophrenia.

I did look for trials in children with Down Syndrome, since here is a direct link to Alzheimer’s, but there is just a trial in adults in progress.

There was an early trial in typical adults which is interesting since it found not only a cognitive improvement but also improved mood, so perhaps it should be trialed in adults with depression.  In the US, interestingly, T3 thyroid hormone is sometimes given off-label for depression and some antidepressants increase the conversion of the pro-hormone T4 to T3 in the brain.  I think central hypothyroidism is likely a feature of some neurological disorders, as I proposed in an earlier post.

I think it would be well worth trialing intranasal insulin in idiopathic Autism and, separately, idiopathic Asperger’s.  I am surprised nobody has done it. I really think Autism and Asperger’s  should be separated, since while we sometimes see the same therapy helps in both, sometimes there are Asperger-specific therapies, like Baclofen.

A small number of readers of this blog do follow the science and engage in some experimentation at home.  I think given what some people have already tried, intranasal insulin is not at all far fetched, you just need a metered dose nasal spray, insulin and the correct amount of dilutant/diluent, as in the trials.

Insulin and IGF-1 (insulin-like growth factor 1)

There are autism trials underway using subcutaneous injections of IGF-1 and also oral IGF-1 analogs.

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,

Insulin levels affect levels of growth hormone (GH) and IGF-1.

We know that various growth factors (NGF, BDNF, IGF-1 etc.) in people with autism can be disturbed, but there is both hypo and hyper.

We also know that the level of hormones measured in the blood can be very different to those in the brain/CNS.  This means that having blood tests indicating  high serotonin, thyroid T3, IGF-1 etc. does not tell you anything about the level within the brain.  Quite possibly they may be the opposite.

It would seem to be hugely preferable to target the brain directly, rather than the whole body.

The lack of side effects in the numerous studies of intranasal insulin is very encouraging.

Healthy Neurotypical Adults

Intranasal insulin improves memory in humans

Declarative memory in humans without causing systemic side effects like hypoglycaemia. The improvement of memory in the eighth week of treatment corroborates previous findings of improved memory function following acute intravenous administration of the peptide both in healthy subjects (Kern et al., 2001) and in patients with Alzheimer’s disease (Craft et al., 1999). In addition, intranasal insulin positively affected mood in our subjects. The improving effect of subchronic intranasal insulin administration appeared to be specific for hippocampus dependent declarative memory.

Our subjects in the insulin group also expressed enhanced mood. Acute intranasal intake of insulin enhanced the feelings of well-being and self-confidence, which is in accordance with previous results (Kern et al., 1999).

In summary our data indicate that prolonged intranasal intake of insulin improves both consolidation of words and general mood. These beneficial findings suggest intranasal administration of insulin as a potential treatment in patients showing memory deficits in conjunction with a lack of insulin, such as in Alzheimer’s disease

Adults with Schizophrenia

No effect of adjunctive, repeated-dose intranasal insulin treatment on psychopathology and cognition in patients with schizophrenia.

Abstract

OBJECTIVE:

This study examined the effect of adjunctive intranasal insulin therapy on psychopathology and cognition in patients with schizophrenia.

METHODS:

Each subject had a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of schizophrenia or schizoaffective disorder and been on stable antipsychotics for at least 1 month. In an 8-week randomized, double-blind, placebo-controlled study, subjects received either intranasal insulin (40 IU 4 times per day) or placebo. Psychopathology was assessed using the Positive and Negative Syndrome Scale and the Scale for Assessment of Negative Symptoms. A neuropsychological battery was used to assess cognitive performance. The assessment for psychopathology and cognition was conducted at baseline, week 4, and week 8.

RESULTS:

A total of 45 subjects were enrolled in the study (21 in the insulin group and 24 in the placebo group). The mixed model analysis showed that there were no significant differences between the 2 groups at week 8 on various psychopathology and cognitive measures (P > 0.1).

CONCLUSIONS:

Adjunctive therapy with intranasal insulin did not seem to be beneficial in improving schizophrenia symptoms or cognition in the present study. The implications for future studies were discussed.

Adults with Bipolar

A randomized, double-blind, controlled trial evaluating the effect of intranasal insulin on neurocognitive function in euthymic patients with bipolar disorder.

 

Abstract

BACKGROUND:

Neurocognitive deficits are prevalent, persistent, and implicated as mediators of functional impairment in adults with bipolar disorder. Notwithstanding progress in the development of pharmacological treatments for various phases of bipolar disorder, no available treatment has been proven to be reliably efficacious in treating neurocognitive deficits. Emerging evidence indicates that insulin dysregulation may be pertinent to neurocognitive function. In keeping with this view, we tested the hypothesis that intranasal insulin administration would improve measures of neurocognitive performance in euthymic adults with bipolar disorder.

METHODS:

Sixty-two adults with bipolar I/II disorder (based on the Mini International Neuropsychiatric Interview 5.0) were randomized to adjunctive intranasal insulin 40 IU q.i.d. (n = 34) or placebo (n = 28) for eight weeks. All subjects were prospectively verified to be euthymic on the basis of a total score of ≤ 3 on the seven-item Hamilton Depression Rating Scale (HAMD-7) and ≤ 7 on the 11-item Young Mania Rating Scale (YMRS) for a minimum of 28 consecutive days. Neurocognitive function and outcome was assessed with a neurocognitive battery.

RESULTS:

There were no significant between-group differences in mean age of the subjects {i.e., mean age 40 [standard deviation (SD) = 10.15] years in the insulin and 39 [SD = 10.41] in the placebo groups, respectively}. In the insulin group, n = 27 (79.4%) had bipolar I disorder, while n = 7 (21.6%) had bipolar II disorder. In the placebo group, n = 25 (89.3%) had bipolar I disorder, while n = 3 (10.7%) had bipolar II disorder. All subjects received concomitant medications; medications remained stable during study enrollment. A significant improvement versus placebo was noted with intranasal insulin therapy on executive function (i.e., Trail Making Test-Part B). Time effects were significant for most California Verbal Learning Test indices and the Process Dissociation Task-Habit Estimate, suggesting an improved performance from baseline to endpoint with no between-group differences. Intranasal insulin was well tolerated; no subject exhibited hypoglycemia or other safety concerns.

CONCLUSIONS:

Adjunctive intranasal insulin administration significantly improved a single measure of executive function in bipolar disorder. We were unable to detect between-group differences on other neurocognitive measures, with improvement noted in both groups. Subject phenotyping on the basis of pre-existing neurocognitive deficits and/or genotype [e.g., apolipoprotein E (ApoE)] may possibly identify a more responsive subgroup

Children with Phelan-McDermid Syndrome 

22q13 deletion syndrome is a genetic disorder caused by deletions or rearrangements on the q terminal end (long arm) of chromosome 22. Any abnormal genetic variation in the q13 region that presents with significant manifestations typical of a terminal deletion should be diagnosed as 22q13 deletion syndrome. 22q13 deletion syndrome is often placed in the more general category of Phelan-McDermid Syndrome (abbreviated PMS), which includes some mutations and microdeletions. 

Physical

·         Absent to severely delayed speech: 99%

·         Normal to accelerated growth: 95%

·         High tolerance to pain: 77%

·         Hypotonia (poor muscle tone): 75%

·         Dysplastic toenails: 73%

·         Long eyelashes: 73%

·         Poor thermoregulation: 68%

·         Prominent, poorly formed ears: 65%

·         Large or fleshy hands: 63%

·         Pointed chin: 62%

·         Dolichocephaly (elongated head): 57%

·         Ptosis (eyelid) (droopy eyelids): 57%

·         Gastroesophageal reflux: 42%

·         Epileptic seizures: 27%

·         Kidney problems: 26%

·         Delayed ability to walk: 18%

Behavioral

·         Chewing on non food items: 85%

·         Delayed or unreliable toileting: 76%

·         Impulsive behaviors: 47%

·         Biting (self or others): 46%

·         Problems sleeping: 46%

·         Hair pulling: 41%

·         Autistic behaviors: 31%

·         Episodes of non-stop crying before age 5: 30%

·         Teeth grinding: (unknown) %

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

 

BACKGROUND:

The 22q13 deletion syndrome (Phelan-McDermid syndrome) is characterised by a global developmental delay, absent or delayed speech, generalised hypotonia, autistic behaviour and characteristic phenotypic features. Intranasal insulin has been shown to improve declarative memory in healthy adult subjects and in patients with Alzheimer disease.

AIMS:

To assess if intranasal insulin is also able to improve the developmental delay in children with 22q13 deletion syndrome.

METHODS:

We performed exploratory clinical trials in six children with 22q13 deletion syndrome who received intranasal insulin over a period of 1 year. Short-term (during the first 6 weeks) and long-term effects (after 12 months of treatment) on motor skills, cognitive functions, or autonomous functions, speech and communication, emotional state, social behaviour, behavioural disorders, independence in daily living and education were assessed.

RESULTS:

The children showed marked short-term improvements in gross and fine motor activities, cognitive functions and educational level. Positive long-term effects were found for fine and gross motor activities, nonverbal communication, cognitive functions and autonomy. Possible side effects were found in one patient who displayed changes in balance, extreme sensitivity to touch and general loss of interest. One patient complained of intermittent nose bleeding.

CONCLUSIONS:

We conclude that long-term administration of intranasal insulin may benefit motor development, cognitive functions and spontaneous activity in children with 22q13 deletion syndrome.

For intranasal administration, insulin (40 IU/ml; Actrapid, Novo Nordisk, Mainz, Germany) was diluted with 0.9% saline solution to a concentration of 20 IU/ml so that each 0.1 ml puff with the nasal atomizer (Aero Pump, Hochheim, Germany) contained a dose of 2 IU insulin. Subjects received one dose of 2 IU insulin per day during the first 3 days according to the standard subcutaneous insulin therapy in children with type 1 diabetes mellitus. In three-day intervals, administration was increased gradually, until the final dosage of about 0.5-1.5 IU/kg/d (TID)

As with idiopathic autism there is interest in using the related IGF-1 as a therapy.

A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome

Background

Autism spectrum disorder (ASD) is now understood to have multiple genetic risk genes and one example is SHANK3. SHANK3 deletions and mutations disrupt synaptic function and result in Phelan-McDermid syndrome (PMS), which causes a monogenic form of ASD with a frequency of at least 0.5% of ASD cases. Recent evidence from preclinical studies with mouse and human neuronal models of SHANK3 deficiency suggest that insulin-like growth factor-1 (IGF-1) can reverse synaptic plasticity and motor learning deficits. The objective of this study was to pilot IGF-1 treatment in children with PMS to evaluate safety, tolerability, and efficacy for core deficits of ASD, including social impairment and restricted and repetitive behaviors.

Methods

Nine children with PMS aged 5 to 15 were enrolled in a placebo-controlled, double-blind, crossover design study, with 3 months of treatment with IGF-1 and 3 months of placebo in random order, separated by a 4-week wash-out period.

Results

Compared to the placebo phase, the IGF-1 phase was associated with significant improvement in both social impairment and restrictive behaviors, as measured by the Aberrant Behavior Checklist and the Repetitive Behavior Scale, respectively. IGF-1 was found to be well tolerated and there were no serious adverse events in any participants.

Conclusions

This study establishes the feasibility of IGF-1 treatment in PMS and contributes pilot data from the first controlled treatment trial in the syndrome. Results also provide proof of concept to advance knowledge about developing targeted treatments for additional causes of ASD associated with impaired synaptic development and function.

Drug administration

IGF-1 (Increlex; Ipsen Biopharmaceuticals, Inc) is an aqueous solution for injection containing human insulin-like growth factor-1 (rhIGF-1) produced by recombinant DNA technology. Placebo consisted of saline prepared in identical bottles by the research pharmacy at Mount Sinai. We received an Investigational New Drug exemption from the Food and Drug Administration (#113031) to conduct this trial in children with PMS. Based on the package insert for Increlex, dose titration was initiated at 0.04 mg/kg twice daily by subcutaneous injection, and increased, as tolerated, every week by 0.04 mg/kg per dose to a maximum of 0.12 mg/kg twice daily. This titration was justified based on our preclinical data, which indicated that 0.24 mg/kg/day is effective in reversing electrophysiological deficits whereas 0.12 mg/kg/day was not as effective[21]. We aimed to reach the therapeutic dose as quickly as is safe and tolerated in order to allow maximum time for clinical improvement. Doses could be decreased according to tolerability by 0.04 mg/kg per dose. Medication was administered twice daily with meals, and preprandial glucose monitoring was performed by parents prior to each injection throughout the treatment period. Parents were carefully trained in finger stick monitoring, symptoms of hypoglycemia, and medication administration.

Down Syndrome

The ongoing Down Syndrome trial is in adults.  As mentioned earlier, a feature of the syndrome is the likely early onset of Alzheimer’s, so not surprisingly if intranasal insulin helps people with Alzheimer’s it makes sense to trial it on people with Down Syndrome.

I think it makes sense to trial it on young people with Down Syndrome, prior to the onset of Alzheimer’s.

Investigation of the Safety of Intranasal Glulisine in Down Syndrome

This study is a single center, randomized, double-blind, placebo-controlled, cross-over pilot study designed to assess the safety of intranasally (IN) delivered glulisine versus placebo in patients with DS. Subjects will be randomized into this cross-over study and within subject comparisons conducted between single treatment of intranasal insulin glulisine and single treatment of intranasal placebo

The SNIFF (Study of Nasal Insulin in the Fight against Forgetfulness) Trials

The large clinical trials all relate to Alzheimer’s.  The big trial, SNIFF INI, will last for 18 months, but they are also making shorter trials using different types of insulin.  There is  SNIFF Quick to test fast acting insulin and SNIFF long to test the long acting type.

SNIFF Quick

SNIFF Long

SNIFF INI

The big 18 month study.

Conclusion

I think in a couple of decade’s time, it will be widely recognized that various physiological states exist in many complex diseases and while it may not be possible to cure those conditions, you can treat those altered physiological states.

In the case of autism those states might include:-

·        Oxidative stress

·        Mitochondrial stress

·        Microglial activation

·        Central hormonal dysfunction

·        Reduced brain insulin sensitivity

·        Impaired remyelination

·        Faulty GABA switch

These altered states are in addition to the specific channelopathies and other dysfunctions a particular person might have.

By applying what is learnt from other diseases we can then better treat the autism variants.  So what eventually develops from MS research in regard to remyelination can be translated to some autism variants, quite possibly that of Hannah Poling (mitochondrial disease, triggered by vaccination).

Reduced brain insulin sensitivity, where present, appears very treatable today.  I suspect some variants of autism do indeed feature reduced brain insulin sensitivity, but others will not.  There is no clever way to predict this, but it looks simple to test.