Treating Rett syndrome, some autism and some dementia via TrkA, TrkB, BDNF, IGF-1, NGF and NDPIH. And logically why Bumetanide really should work in Rett

Source: Rett Syndrome: Crossing the Threshold to Clinical Translation

 

Today’s post is on the one hand very specific to Rett syndrome, but much is applicable to broader autism and other single gene autisms.

Today’s post did start out with the research showing Bumetanide effective in the mouse model of Rett syndrome. This ended up with figuring out why this should have been obvious based on what we already know about growth factors that are disturbed in autism and very much so in Rett.

We even know from a published human case studies that Bumetanide can benefit those with Fragile X and indeed Down syndrome, but the world takes little notice.

If Bumetanide benefits human Rett syndrome would anyone take any notice?  They really should.

To readers of this blog who have a child with Rett, the results really are important.  You can even potentially link the problem symptoms found in Rett to the biology and see how you can potentially treat multiple symptoms with the same drug.

One feature of Rett is breathing disturbances, which typically consist of alternating periods of hyperventilation and hypoventilation.

Our reader Daniel sent me a link to paper that suggest an old OTC cough medicine could be used to treat the breathing issues.

The antitussive cloperastine improves breathing abnormalities in a Rett Syndrome mouse model by blocking presynaptic GIRK channels and enhancing GABA release

Rett Syndrome (RTT) is an X-linked neurodevelopmental disorder caused mainly by mutations in the MECP2 gene. One of the major RTT features is breathing dysfunction characterized by periodic hypo- and hyperventilation. The breathing disorders are associated with increased brainstem neuronal excitability, which can be alleviated with antagonistic agents.

Since neuronal hypoexcitability occurs in the forebrain of RTT models, it is necessary to find pharmacological agents with a relative preference to brainstem neurons. Here we show evidence for the improvement of breathing disorders of Mecp2-null mice with the brainstem-acting drug cloperastine (CPS) and its likely neuronal targets. CPS is an over-the-counter cough medicine that has an inhibitory effect on brainstem neuronal networks. In Mecp2-null mice, CPS (30 mg/kg, i.p.) decreased the occurrence of apneas/h and breath frequency variation. GIRK currents expressed in HEK cells were inhibited by CPS with IC50 1 μM. Whole-cell patch clamp recordings in locus coeruleus (LC) and dorsal tegmental nucleus (DTN) neurons revealed an overall inhibitory effect of CPS (10 μM) on neuronal firing activity. Such an effect was reversed by the GABAA receptor antagonist bicuculline (20 μM). Voltage clamp studies showed that CPS increased GABAergic sIPSCs in LC cells, which was blocked by the GABAB receptor antagonist phaclofen. Functional GABAergic connections of DTN neurons with LC cells were shown.

These results suggest that CPS improves breathing dysfunction in Mecp2-null mice by blocking GIRK channels in synaptic terminals and enhancing GABA release.

  

Cloperastine (CPS) is a central-acting antitussive working on brainstem neuronal networks The drug has several characteristics. 1) It affects the brainstem integration of multiple sensory inputs via multiple sites including K+ channels, histamine and sigma receptors. 2) Its overall effect is inhibitory, suppressing cough and reactive airway signals. 3) With a large safety margin, it has been approved as an over-the-counter medicine in several Asian and European countries.  

With the evidence that DTN cells receive GABAergic recurrent inhibition, we tested whether the inhibitory effect of CPS was caused by enhanced GABAergic transmission. Thus, we recorded the evoked firing activity of DTN cells before and during bath application of CPS in the presence of 20 μM bicuculline. Under this condition, CPS failed to decrease the excitability of DTN neurons (F(1,9) = 0.41, P > 0.05; two‐way repeated measures ANOVA) (n=9) (Fig. 8), indicating that the inhibitory effect relies on GABAA synaptic input 

 

It appeared to me that the breathing issues might be considered as another consequence of the excitatory/inhibitory (E/I) imbalance that is a core feature of much severe autism.

In the case of Rett the lack of BDNF will make any E/I imbalance worse and that by treating the E/I imbalance we will produce the inhibitory effect from GABAa receptors that is needed to ensure correct breathing.  Note that in bumetanide responsive autism there is no inhibitory effect from GABAa receptors, the effect is excitatory.

I did wonder if arrhythmia (irregular heartbeat) is present in Rett, since the breathing problems in Rett are also seen as being caused by a dysfunction in the autonomic nervous system. Arrhythmia is actually a big problem for girls with Rett syndrome.  Regular readers of this blog might then ask about Propranolol, does that help?  It turns out to have been tried and it is not so helpful.  What is effective is another drug we have come across for autism, the sodium channel blocker Phenytoin.  Phenytoin is antiepileptic drug (AED) and it works by blocking voltage gated sodium channels.

Low dose phenytoin was proposed as an autism therapy and a case study was published from Australia. In a separate case study, phenytoin was used to treat self-injury that was triggered by frontal lobe seizures.

When you treat arrhythmia in Rett girls with Phenytoin does it have an impact on their breathing problems?

If you treat the girls with Phenytoin do they still go on to develop epilepsy?

What about if you add treatment with Bumetanide to reduce symptoms of autism? 

Lots of questions looking for answers.

 

What is Rett Syndrome?

Rett syndrome was first identified in the 1950s by Dr Andreas Rett as a disorder that develops in young girls.  Only as recently as 1999 was it determined that the syndrome is caused by a mutation in the MECP2 gene on the X chromosome.  The X chromosome is very important because girls have two copies, but boys have just one.  Rett was an Austrian like many other early researchers in autism like Kanner and Asperger. Even Freud was educated in Vienna. Eugen Bleuler lived pretty close by in Switzerland and he coined the terms schizophrenia, schizoid and autism. 

Rett syndrome is a rare genetic disorder that affects brain development, resulting in severe mental and physical disability.

It is estimated to affect about 1 in 12,000 girls born each year.

Rett is a rare condition, but among these rare conditions it is quite common and so there is a lot of research going on to find treatments.  The obvious one is gene therapy to get the brain to make the missing MeCP2 protein.

Rett syndrome is thankfully rare in absolute terms, but it is one of the best known development conditions that is associated with autism symptoms.

While Rett syndrome may not officially be an ASD in the DSM-5, the link to autism remains. Many children are diagnosed as autistic before the MECP2 mutation is identified and then the diagnosis is revised to RTT/Rett. 

Fragile X  syndrome (FXS), on the other hand, is the most common inherited cause of intellectual disability (ID), as well as the most frequent single gene type of autism.

In the meantime, the logical strategy is to treat the downstream consequences of the mutated gene. Much is known about these downstream effects and there overlaps with some broader autism and indeed dementia.

One area known to be disturbed in Rett, some other autisms and dementia is growth factors inside the brain. The best known growth factors are IGF-1 (Insulin-like Growth Factor 1), BDNF (brain-derived neurotrophic factor) and my favorite NGF (Nerve growth factor).

Without wanting to get too complicated we need to note that BDNF acts via a receptor called TrkB.  You can either increase BDNF or just find something else to activate TrkB, as pointed out to me by Daniel.

For readers whose children respond to Bumetanide they are benefiting from correcting elevated levels of chloride in neurons. Too much had been entering by the transporter NKCC1 and too little exiting via KCC2.

One of the effects of having too little BDNF and hence not enough activation of TrkB is that chloride becomes elevated in neurons.  If you do not activate TrkB you do not get enough KCC2, which is what allows chloride to exit neurons.

To what extent would TrkB activation be an alternative/complement to bumetanide in broader autism?

To what extent would TrkB activation be success in treating some types of chronic pain (where KCC2 is known to be down regulated)?

Low levels of BDNF are a feature of Rett and much dementia.

So you would want to:

·        Increase BDNF

·        Activate TRKB with something else

·        Block NKCC2 to compensate for the lack of KCC2

Note that BDNF is not reduced in all types of autism, just in a sub-group.

I note that there already is solid evidence in the research:-

Restoration of motor learning in a mouse model of Rett syndrome following long-term treatment with a novel small-molecule activator of TrkB

Reduced expression of brain-derived neurotrophic factor (BDNF) and impaired activation of the BDNF receptor, tropomyosin receptor kinase B (TrkB; also known as Ntrk2), are thought to contribute significantly to the pathophysiology of Rett syndrome (RTT), a severe neurodevelopmental disorder caused by loss-of-function mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). Previous studies from this and other laboratories have shown that enhancing BDNF expression and/or TrkB activation in Mecp2-deficient mouse models of RTT can ameliorate or reverse abnormal neurological phenotypes that mimic human RTT symptoms. The present study reports on the preclinical efficacy of a novel, small-molecule, non-peptide TrkB partial agonist, PTX-BD4-3, in heterozygous female Mecp2 mutant mice, a well-established RTT model that recapitulates the genetic mosaicism of the human disease. PTX-BD4-3 exhibited specificity for TrkB in cell-based assays of neurotrophin receptor activation and neuronal cell survival and in in vitro receptor binding assays. PTX-BD4-3 also activated TrkB following systemic administration to wild-type and Mecp2 mutant mice and was rapidly cleared from the brain and plasma with a half-life of ∼2 h. Chronic intermittent treatment of Mecp2 mutants with a low dose of PTX-BD4-3 (5 mg/kg, intraperitoneally, once every 3 days for 8 weeks) reversed deficits in two core RTT symptom domains – respiration and motor control – and symptom rescue was maintained for at least 24 h after the last dose. Together, these data indicate that significant clinically relevant benefit can be achieved in a mouse model of RTT with a chronic intermittent, low-dose treatment paradigm targeting the neurotrophin receptor TrkB. 

Early alterations in a mouse model of Rett syndrome: the GABA developmental shift is abolished at birth

Genetic mutations of the Methyl-CpG-binding protein-2 (MECP2) gene underlie Rett syndrome (RTT). Developmental processes are often considered to be irrelevant in RTT pathogenesis but neuronal activity at birth has not been recorded. We report that the GABA developmental shift at birth is abolished in CA3 pyramidal neurons of Mecp2^−/y mice and the glutamatergic/GABAergic postsynaptic currents (PSCs) ratio is increased. Two weeks later, GABA exerts strong excitatory actions, the glutamatergic/GABAergic PSCs ratio is enhanced, hyper-synchronized activity is present and metabotropic long-term depression (LTD) is impacted. One day before delivery, maternal administration of the NKCC1 chloride importer antagonist bumetanide restored these parameters but not respiratory or weight deficits, nor the onset of mortality. Results suggest that birth is a critical period in RTT with important alterations that can be attenuated by bumetanide raising the possibility of early treatment of the disorder.

    

The GABA Polarity Shift and Bumetanide Treatment: Making Sense Requires Unbiased and Undogmatic Analysis

 

GABA depolarizes and often excites immature neurons in all animal species and brain structures investigated due to a developmentally regulated reduction in intracellular chloride concentration ([Cl⁻]_i) levels. The control of [Cl⁻]_i levels is mediated by the chloride cotransporters NKCC1 and KCC2, the former usually importing chloride and the latter exporting it. The GABA polarity shift has been extensively validated in several experimental conditions using often the NKCC1 chloride importer antagonist bumetanide. In spite of an intrinsic heterogeneity, this shift is abolished in many experimental conditions associated with developmental disorders including autism, Rett syndrome, fragile X syndrome, or maternal immune activation. Using bumetanide, an EMA- and FDA-approved agent, many clinical trials have shown promising results with the expected side effects. Kaila et al. have repeatedly challenged these experimental and clinical observations. Here, we reply to the recent reviews by Kaila et al. stressing that the GABA polarity shift is solidly accepted by the scientific community as a major discovery to understand brain development and that bumetanide has shown promising effects in clinical trials.

 

Back in 2013 a case study was published showing Bumetanide worked for a boy with Fragile X syndrome. A decade later and still nobody has looked to see if it works in all Fragile X. 

Treating Fragile X syndrome with the diuretic bumetanide: a case report

https://pubmed.ncbi.nlm.nih.gov/23647528/

We report that daily administration of the diuretic NKCC1 chloride co-transporter, bumetanide, reduces the severity of autism in a 10-year-old Fragile X boy using CARS, ADOS, ABC, RDEG and RRB before and after treatment. In keeping with extensive clinical use of this diuretic, the only side effect was a small hypokalaemia. A double-blind clinical trial is warranted to test the efficacy of bumetanide in FRX.

 

What do Rett syndrome and Fragile X have in common? 

In a healthy mature neuron the level of chloride needs to be low for it to function correctly (the neurotransmitter GABA to be inhibitory).

 

Rett and Fragile X are part of a large group of conditions that feature elevated levels of chloride in neurons.

 

Elevated chloride in neurons is treatable.

 

Is Bumetanide a cure for Rett syndrome, or Fragile X?

No it is not, but it is a step in that direction because it reverses a key defect present in at least some Rett and some Fragile X.

In the mouse model of Rett, bumetanide corrected some, but not all the problems caused by the loss of function of the MECP2 gene.

 

Moving on to IGF-1

IGF-1 is a growth hormone with multiple functions throughout aging. Production of IGF-1 is stimulated by GH (growth hormone).

The lowest levels occur in infancy and old age and highest levels occur around the growth spurt before puberty.

Girls with Turner syndrome, lack their second X chromosome and this causes a lack of growth hormones and female hormones. They end up with short stature and with features of autism. Treatment is possible with GH or indeed IGF-1.

In dementia one strategy is to increase IGF-1.  This same strategy is also being applied to single gene autisms like Rett and Pitt Hopkins.

Trofinetide and NNZ-2591 are improved synthetic analogues of peptides that occur naturally in the brain and are related to IGF-1. Trofinetide is being developed to treat Rett and Fragile X syndromes, NNZ-2591 is being developed to treat Angelman, Phelan-McDermid, Pitt Hopkins and Prader-Willi syndromes.

 

NGF (nerve growth factor)

Nerve growth factor does what it says (boosting nerve growth), plus much more. NGF plays a key role in the immune system, it is produced in mast cells, and it plays a role in how pain in perceived.

NGF acts via NGF receptors, not surprisingly, but also via TrkA receptors. We saw earlier in this post that BDNF acts via TrkB receptors.

Once NGF binds to the TrkA receptor it triggers a cascade of signalling via  the Ras/MAPK pathway and the PI3K/Akt pathway.  Both pathways relate to autism and Ras itself can play a role in intellectual disability. 

These are also cancer pathways and indeed NGF seems to play a role.  Beta cells in the pancreas produce insulin and these beta cells have TrkA receptors. In type 1 diabetes these beta cells die.  Beta cells need NGF to activate their TrkA receptors to survive.

Clearly for multiple reasons you need plenty of NGF.

Lack of NGF would be one cause of dementia and that is why Rita Levi-Montalcini choose to self-treat with NGF eye drops for 30 years. Rita won a Nobel prize for discovering NGF.

In Rett syndrome we know that the level of NGF is very low in the brain.

Logical therapies for Rett would seem to include:

·        NGF itself, perhaps taken as eye drops, but tricky to administer

·        A TrkA agonist, that would mimic the effect of NGF

·        The traditional medicinal mushroom  Lion’s Mane (Hericium erinaceus) 

We should note that effect of NGF acting via TrkA is mainly in the peripheral nervous system, not the brain.

It has long been known that Lions’ Mane (Hericium erinaceus) increases NGF but it was not clear why.  This has very recently been answered.

The active chemical has been identified to be N-de phenylethyl isohericerin (NDPIH).

The opens the door to synthesizing NDPIH as drug to treat a wide range of conditions from Alzheimer’s to Rett. 

Mushrooms Magnify Memory by Boosting Nerve Growth  

Active compounds in the edible Lion’s Mane mushroom can help promote neurogenesis and enhance memory, a new study reports. Preclinical trials report the compound had a significant impact on neural growth and improved memory formation. Researchers say the compound could have clinical applications in treating and preventing neurodegenerative disorders such as Alzheimer’s disease.

Professor Frederic Meunier from the Queensland Brain Institute said the team had identified new active compounds from the mushroom, Hericium erinaceus.

“Extracts from these so-called ‘lion’s mane’ mushrooms have been used in traditional medicine in Asian countries for centuries, but we wanted to scientifically determine their potential effect on brain cells,” Professor Meunier said.

“Pre-clinical testing found the lion’s mane mushroom had a significant impact on the growth of brain cells and improving memory.

“Laboratory tests measured the neurotrophic effects of compounds isolated from Hericium erinaceus on cultured brain cells, and surprisingly we found that the active compounds promote neuron projections, extending and connecting to other neurons.

“Using super-resolution microscopy, we found the mushroom extract and its active components largely increase the size of growth cones, which are particularly important for brain cells to sense their environment and establish new connections with other neurons in the brain.” 

 

Hericerin derivatives activates a pan‐neurotrophic pathway in central hippocampal neurons converging to ERK1/2 signaling enhancing spatial memory

The traditional medicinal mushroom Hericium erinaceus is known for enhancing peripheral nerve regeneration through targeting nerve growth factor (NGF) neurotrophic activity. Here, we purified and identified biologically new active compounds from H. erinaceus, based on their ability to promote neurite outgrowth in hippocampal neurons. N-de phenylethyl isohericerin (NDPIH), an isoindoline compound from this mushroom, together with its hydrophobic derivative hericene A, were highly potent in promoting extensive axon outgrowth and neurite branching in cultured hippocampal neurons even in the absence of serum, demonstrating potent neurotrophic activity. Pharmacological inhibition of tropomyosin receptor kinase B (TrkB) by ANA-12 only partly prevented the NDPIH-induced neurotrophic activity, suggesting a potential link with BDNF signaling. However, we found that NDPIH activated ERK1/2 signaling in the absence of TrkB in HEK-293T cells, an effect that was not sensitive to ANA-12 in the presence of TrkB. Our results demonstrate that NDPIH acts via a complementary neurotrophic pathway independent of TrkB with converging downstream ERK1/2 activation. Mice fed with H. erinaceus crude extract and hericene A also exhibited increased neurotrophin expression and downstream signaling, resulting in significantly enhanced hippocampal memory. Hericene A therefore acts through a novel pan-neurotrophic signaling pathway, leading to improved cognitive performance.

 

Since the discovery of the first neurotrophin, NGF, more than 70 years ago, countless studies have demonstrated their ability to promote neurite regeneration, prevent or reverse neuronal degeneration and enhance synaptic plasticity. Neurotrophins have attracted the attention of the scientific community in the view to implement therapeutic strategies for the treatment of a number of neurological disorders. Unfortunately, their actual therapeutic applications have been limited and the potential use of their beneficial effects remain to be exploited. Neurotrophins, for example, have poor oral bioavailability, and very low stability in serum, with half-lives in the order of minutes  as well as minimal BBB permeability and restricted diffusion within brain parenchyma. In addition, their receptor signaling networks can confer undesired off-target effects such as pain, spasticity and even neurodegeneration. As a consequence, alternative strategies to increase neurotrophin levels, improve their pharmacokinetic limitations or target specific receptors have been developed. Identification of bioactive compounds derived from natural products with neurotrophic activities also provide new hope in the development of sustainable therapeutical interventions. Hericerin derivative are therefore attractive compounds for their ability to promote a pan-neurotrophic effect with converging ERK1/2 downstream signaling pathway and for their ability to promote the expression of neurotrophins. Further work will be needed to find the direct target of Hericerin capable of mediating such a potent pan-neurotrophic activity and establish whether this novel pathway can be harnessed to improve memory performance and for slowing down the cognitive decline associated with ageing and neurodegenerative diseases.

 

What this means is that there are 2 good reasons why Lion’s Mane should be helpful in Rett syndrome, both increasing BDNF and NGF.

  

Conclusion

Interestingly, one of the above papers is co-authored by a researcher from the European Brain Research Institute, founded by Rita Levi-Montalcini, the Nobel laureate who discovered NGF (Nerve growth factor). My top pick to test next in Rett syndrome would be NGF. Administration would have to follow Rita’s own example and be in the form of eye drops or follow the Lion’s Mane option, that has recently been further validated.

Rett syndrome is very well documented and many researchers are engaged in studying it.

As with broader autism, the problem is translating all the research into practical therapy today.

Clearly polytherapy will be required.

More than one type of neuronal hyperexcitability seems to be in play.

It looks like one E/I imbalance is the bumetanide responsive kind, that can be treated and will reduce autism symptoms and improve learning skills.  Then we have the hypoventilation/apnea for which Cloperastine looks a fair bet.  For the arrhythmia we have Phenytoin.  If there are still seizures after all that therapy it looks like sodium valproate is the standard treatment for Rett.

Sodium valproate is also an HDAC inhibitor and so has possibly beneficial epigenetic effects as a bonus.

I have always liked the idea of the Lion’s Mane mushrooms as a means to increase NGF (Nerve growth factor).  In today’s post we saw that it is the NDPIH from the mushrooms that acts to increase both BDNF and NGF.  You would struggle to buy NDPIH but you can buy these mushrooms. I did once buy the supplement version of these mushrooms and it was contaminated, so I think the best bet is the actual chemical or the actual mushroom.  One reader did write in once who is a big consumer of these mushrooms.

 

Lion's Mane Mushroom

Source: Igelstachelbart Nov 06

 

A Trk-B agonist that can penetrate the blood brain barrier would look a good idea.  There are some sold by the nootropic people.

7,8-dihydroxyflavone is such an agonist that showed a benefit in the mouse model.

 

7,8-dihydroxyflavone exhibits therapeutic efficacy in a mouse model of Rett syndrome

Following weaning, 7,8-DHF was administered in drinking water throughout life. Treated mutant mice lived significantly longer compared with untreated mutant littermates (80 ± 4 and 66 ± 2 days, respectively). 7,8-DHF delayed body weight loss, increased neuronal nuclei size and enhanced voluntary locomotor (running wheel) distance in Mecp2 mutant mice. In addition, administration of 7,8-DHF partially improved breathing pattern irregularities and returned tidal volumes to near wild-type levels. Thus although the specific mechanisms are not completely known, 7,8-DHF appears to reduce disease symptoms in Mecp2 mutant mice and may have potential as a therapeutic treatment for RTT patients.

Rett syndrome also features mitochondrial dysfunction and a variant of metabolic syndrome.  We have quite a resource available from broader autism, not much of it seems to have been applied in Rett.

You can see that in Rett less oxygen is available due to breathing issues and yet more oxygen is required due to “faulty” mitochondria. 

“Intensified mitochondrial O2 consumption, increased mitochondrial ROS generation and disturbed redox balance in mitochondria and cytosol may represent a causal chain, which provokes dysregulated proteins, oxidative tissue damage, and contributes to neuronal network dysfunction in RTT.”

https://www.frontiersin.org/articles/10.3389/fphys.2019.00479/full#:~:text=Rett%20syndrome%20(RTT)%2C%20an,inner%20membrane%20is%20leaking%20protons.

 

We have seen in this blog that 2 old drugs exist to increase oxygen levels in blood.  The Western world has Diamox (Acetazolamide) and the former soviet world has Mildronate/Meldonium. Mildronate also was suggested to have some wider potential benefit to mitochondria.

Rett is proposed as a neurological disorder with metabolic components, so based on what we have seen in this blog, you would think along the lines of Metformin, Pioglitazone and a lipophilic statin (Atorvastatin, Simvastatin or Lovastatin). 

The Anti-Diabetic Drug Metformin Rescues Aberrant Mitochondrial Activity and Restrains Oxidative Stress in a Female Mouse Model of Rett Syndrome

Statins improve symptoms of Rett syndrome in mice

The ultimate Rett cure will be one of the new gene therapies given to a baby before any significant progression of the disorder has occurred.

For everyone else, it looks like there is scope to develop a pretty potent individualized polytherapy, just by applying the very substantial knowledge that already exists in the research.

Good luck to Daniel and all the others seeking answers.

 

Will Anavex for “Autisms” be worth the wait and the price, compared to Russian OTC Afobazole?

US-Russia cooperation has long been possible in Space, but not so often in Medicine. NASA reportedly pays Russia $85 million per astronaut to go the International Space Station (ISS).  The US Space Shuttle program ended in 2011, leaving a Russian Soyuz rocket the only way to the ISS.

This post comes ahead of the dietary autism post, awaited by Tanya.  It really is just a brief follow-on from the previous post. I have only just come across Anavex, which does add weight to the first post on sigma-1R.
                                                                                                               

Hundreds of millions of dollars are being spent in the US to develop a safe sigma-1R agonist (Anavex 2-73). This drug is being trialed in various autisms (Rett, Fragile X and Angelman syndromes), Parkinson’s and Alzheimer’s.

In the last post I wrote about a cheap OTC anxiety drug from Russia, called Afobazole, that appears to be a safe sigma-1R agonist.  This drug has also recently been trialed in autism and Parkinson’s - the same targets as Anavex.

I did make the point in my original sigma-1 post that I am interested in existing therapies, rather than potential ones, so I did not include Anavex, or any other research drug, in that post. Anavex is nonetheless interesting, because their research studies further support the suggestion that targeting ER stress via sigma-1 is an interesting avenue to pursue.  

ERStress and Protein Misfolding in Autism (and IP3R again) and perhaps what to do about it - Activation of Sigma-1 Chaperone Activity by Afobazole?

Anavex is claiming precision medicine, but in fact sigma-1R agonists appear more like the opposite, at least in terms of who you target.  The majority of both common and rare neurological disorders look like they should benefit from reducing ER Stress (from whatever cause); it is a shared feature.  So it looks more like a shotgun approach; that is actually a good thing, if it were to drive the price down.

What is needed is an affordable, effective, mass market drug; not an ultra expensive pill just for Rett Syndrome and perhaps a different colour version for Angelman's Syndrome.

Which will prove effective - Anavex or Afobazole? Or perhaps neither.

Having already made the case for Soyuz in my earlier post, here is the case for NASA, and for those with NASA-sized budgets, courtesy of  https://www.anavex.com/

Animal Study Details Motor, Sensory and Respiratory Benefits of Anavex 2-73, Supporting Phase 2 Trials

Treatment with Anavex 2-73 was seen to improve motor skills, acoustic responses and visual acuity in a mouse model of Rett syndrome, supporting ongoing Phase 2 studies in patients.

Its use also helped to lessen abnormal movements and ease breathing in these mice, its researchers said.

The study, “ANAVEX®2-73 (blarcamesine), a Sigma-1 receptor agonist, ameliorates neurologic impairments in a mouse model of Rett syndrome,” was published in the journal Pharmacology Biochemistry and Behavior.

Anavex 2-73 (blarcamesine) is an oral investigational therapy developed by Anavex Life Sciences that works by activating the sigma-1 receptor (S1R), a protein involved in the correct folding of other proteins.

S1R activation results in reduced toxic accumulation of misfolded proteins, as well as lesser dysfunction in mitochondria (a cell’s “powerhouse”), oxidative stress and neuroinflammation, all involved in Rett syndrome. (Oxidative stress is an imbalance between the production of free radicals — potentially harmful molecules associated with a number of diseases — and the generation of antioxidant defenses.)

Researchers at Anavex, assisted by PsychoGenics, evaluated the potential treatment’s specific effects on Rett symptoms in a validated mouse model.

They assessed motor function (balance, motor coordination, locomotion, and abnormal movements or stereotypies), sensory function (reflex responses to sound stimuli and visual clarity), and respiratory function.

Motor and sensory functions were assessed in younger mice, while visual acuity and breathing were measured in older animals.

Results showed that Anavex 2-73 significantly eased motor dysfunction, and deficits in acoustic and visual responses compared to mice given a placebo.

Anavex 2-73 also induced a significant reduction in two distinctive features of Rett syndrome found in these mice: hind-limb clasping (an abnormal posture comparable to hand stereotypies in people with Rett), and apnea (involuntary breath-holding) that is the most concerning breathing abnormality in Rett syndrome, the researchers said. These improvements were mainly dependent on treatment dose and duration.

“In conclusion, the data demonstrate that [Anavex 2-73] is effective in ameliorating multiple neurobehavioral phenotypes in [Rett] mice,” the researchers wrote. “In line with previous animal and human studies [in other neurodegenerative diseases], [Anavex 2-73] also showed a good safety profile,” they added.

These data served as a proof-of-concept for an ongoing safety and efficacy Phase 2 trial called RS-001 (NCT03758924, still enrolling) in the U.S., and for the Phase 2 AVATAR study (NCT03941444) in Australia. These trials together will evaluate Anavex 2-73 in up to 51 women with Rett syndrome.

Conclusion

It may be that Anavex is far superior to the cheap Afobazole. Like the space shuttle was far more advanced than the Soyuz. 

But what if the cheap Afobazole is quite good enough?  Like the cramped, but reliable Soyuz rocket.

Anavex/Afobazole will not cure any severe neurological condition, just improve it, so it will need to be part of a polytherapy. That means the patient will need to be able to afford multiple drugs, somehow.

Coming back to those autisms, what if your daughter has Rett Syndrome, or son has Fragile-X Syndrome ?  Wait a few years for Anavex and for someone else to pay for it? or make do with some cheap Afobazole?

Education and Autism

This blog mainly concerns personalized medicine, which is a therapy targeted to a specific person, or sub-group.  Personalized medicine can include drugs, OTC supplements, diets and, importantly, non-drug medical therapies like vagal nerve stimulation.  Some non-drug medical therapies were covered in previous posts and others will be covered in future posts.

The other part of the bigger puzzle can be called personalized education; anything from ABA to music therapy to what you do at school.

Eleven years ago, when starting with our first ABA consultant, just about his first question was “are you following any special diets or biomedical therapies”. He was clearly against such therapies, seeing them as a big distraction from the all-important ABA and Verbal Behavior (VB).  He did indeed have a point, you do have to focus your attention on multiple tasks and avoid being obsessed with vaccines, gluten or candida, as some people appear to be.

ABA does have its limits, as our first ABA consultant found with his own son. In the case of severe autism it may well help a lot, but it usually is not enough. Rather ironically this ABA consultant eventually came back to me years later to ask about personalized medicine.

Some people report terrible experiences with ABA and, if these are genuine, I think there must be some terrible ABA therapists out there. We had very positive experiences with ABA consultants and our home-trained therapists. 

Education

In the case of Monty, aged 15 with autism, he started with very personalized education and only much later, at 9 years old, did we add personalized medicine.

It is pretty clear than in cases of severe autism you need all the help you can get and so as to achieve a  relatively good life (the palm tree by the beach, in the above graphic); you need personalized education and personalized medicine.

Education of typical children

For some years I was a school governor at an international school and so I got to know many different teachers, different educational systems and curricula.

When schooling kids with autism the choice is normally between mainstream school, special school or home schooling. In some countries home schooling is illegal.

Mainstream schooling varies greatly from country to country. Most active autism parents seem to be North American and they likely do not realize how lucky they are to have a pretty easy school curriculum, which lends itself to less able learners.

In some other countries the standard of maths and science is very much higher and school is really geared up to benefit the most able. Anyone of average ability, or below, very often gets left behind.

The level of selection in schools is also important and highly variable. In some countries kids get separated at age of 10-12 into those who are expected to do well and becomes doctors/scientists/ lawyers and those who will end up with vocational training rather than a degree.

In other countries you get a genuine mix of abilities all the way up through high school.

Poor Learners

I had a visit recently from a friend of mine who runs an organisation in Austria that tries to attract top achievers from university to spend two or more years teaching in the country’s worst performing schools, before starting their intended high-flying careers. It is part of an international group doing the same thing across the world. They seem to be doing well and the schools perform much better with their energetic young teachers.

What was interesting to hear was just how bad the standards are at some of these schools.  A significant minority of 12 years old kids are functionally illiterate. One reason is that they have many immigrant children who do not speak German at home, did not speak German in Kindergarten and now sit in a class that is 80% non-native German speakers. The end result is that they cannot write a sentence in German, even though they might have lived all their life in Austria. So much for inclusion/integration.

Interestingly, my friend told me that in Austria, almost no one knows that Hans Asperger was an Austrian.  I did not mention that some Americans are worrying about whether Asperger was a Nazi.  Andreas Rett, another Viennese doctor, whose name was given to Rett syndrome by the English-speaking world 17 years after he described it in the German literature, is another forgotten Austrian. Rett actually was a Nazi, so I suppose some people will want to rename that syndrome, when they figure this out. Leo Kanner was really Austro-Hungarian, being born in Lviv. Kanner was Jewish, so definitely not a Nazi. So many Austrians connected to autism and yet nowadays the German speaking world contributes almost nothing to autism research. I will leave you to draw your own conclusions.

How Austria can restore its status as a center of autism research

Back to education.

The top performers educationally are usually Singapore, where they practice old-fashioned education and Finland, where they follow a very enlightened non-pressurizing Scandinavian approach and where school starts at 7 years old.

The maths curriculum and the workbooks from Singapore are widely used by home schoolers around the world and I bought them for my son. 

A suitable learning environment for someone with severe autism

In many developed countries education authorities believe that children with severe autism can be educated in both mainstream classrooms or in special education.

Given just how variable mainstream education is, we should not expect consistent results. For some children inclusive education will work well and for others it might be a disaster.  A lot depends on what you are being included into and you have to be “includable”.

Small classes, with up to 12 kids, that include all abilities and only one special needs learner give the best chance of success, in my opinion.

Classes with 30 kids including 2+ special needs learners are a recipe for failure for all 30 kids.

Special education varies from large groups and a single teacher in some countries to tiny groups and where each child also has their own 1:1 assistant. There is no normal or typical special school.  There are some very good special schools in the United States, but they must cost someone $100,000 a year.

Home schooling is only as effective as how good the “teacher” is.

Parents need to think long and hard about how to educate their child with severe autism and not assume the State will provide them a perfect solution.  The better the education is for typical children, the greater chance you have of good special needs provision. Not surprisingly, special education is good in Scandinavia and terrible in most poor countries.  One of Monty's assistants moved to Norway to be a special needs teacher.

Some people with severe autism will struggle to learn anything, anywhere. These people need personalized medicine or else their 15-18 years spent in “education” is just day-care and a prelude to institutionalization, perhaps with a nice name like a group home.                                      

Personalized Education combined with Personalized Medicine

At the age of 8, after 4 years of intensive ABA-inspired intervention, Monty could not grasp the simplest elements of maths; I mean single digit addition or subtraction using the number line. Language and cognitive function appeared to be immovable barriers to progress.

December 2018 marks six years after starting personalized medicine, and I just learned that Monty’s grade for Maths this term is B+. He could handle the algebra and trigonometry in the end of term test, without any prompting from his assistant.

The addition of personalized medicine has had a transformative effect on cognition.  This continues to surprise people even now. 

Equally encouraging is that Monty has taught himself to swim "properly", he has long been confident in a pool or in the sea, but now at school they go to swim in a full sized pool and get timed swimming laps. Today he was the fastest of two combined classes, that is something else that would not have been expected. 

One autism Grandad we know regards Monty as "80% fixed", but "some problems will always remain"; that is quite a nice summary. It is all relative to what you know, this Grandad only knows really severe autism.  I think many of the parents of the 1 in 40 now diagnosed in the US with "autism" would regard Monty as far from "fixed", but then their kids are fully verbal and have few challenges.  

People with severe autism inevitably plateau at a low cognitive-equivalent age, but it does not have to be like that, if you can treat the underlying biology.  

If you start by treating the biology and fine-tune brain function to the extent that is possible, then you should benefit greatly from all that costly personalized education, that you may or may not get someone else to pay for.

Conclusion

If you have a child with severe autism, life may become a huge challenge. There are all kinds of horror stories you can read about - I suggest you do not dwell on them.  Everyone has options, whether to rely entirely on what you get for free from the State, or whether to apply other methods.

In a resource unconstrained situation, the best outcome is likely to come by combining personalized medicine with personalized education. I can only say that this combination has worked well for us.  In terms of money, it has clearly cost much more than having a typical child, about twice as much. 

If money is tight, start with personalized medicine.

People tend not to put a value on time, but for many time may be the greatest cost. You typically cannot leave a person with severe autism unattended and if they have a complicated schedule, somebody always has to be there and to be able to step in when something gets cancelled, or someone is off sick. 

Until the 1970s, medicine did have a strategy for people with severe autism. It was diagnose, institutionalize as a young child and forget. The Germans added their own variant to this.  Having shut down all the big residential hospitals for mental conditions, there is now often a big gap in provision.  Where do you put adult-sized people with severe autism?  It may not be a problem for those who are docile, but what about those who are not?