Holiday Injection … Done! Getting “Pfizered” for Greece

 

Some parts of the world are trying to get back to some sort of Covid normal, while others are in crisis.  Where we live 40% have been vaccinated and likely 50% have already had the virus.

Monty, aged 17 with ASD, is a big fan of swimming in the sea and where we live that means crossing borders.  Crossing borders is much easier if you have had a Covid-19 vaccine and it looks like for children the best option is the one from Pfizer-BioNTech.  BioNTech is the clever company set up by a Turkish husband and wife team in Germany. They licensed their vaccine to Pfizer for distribution outside of China, in China they have a deal with Fosun Pharma.

Last week Monty had the opportunity, at very short notice, to go and get the Pfizer inoculation. I collected him from school and took him to a clinic in the city centre, that he has never been to and which undoubtedly would have a long line of people queuing outside it.

Monty knows all about injections and syringes, courtesy of his dental marathon a couple of years ago. He even knows about antibodies from Biology classes. The most rational explanation I came up with while driving, for why he was going to see the “doctor” was that it was for his “holiday injection”.  Monty’s school assistant had some more scientific explanations, but the problem is then you are left wondering why you still need to wear a mask at school, after you have been “Pfizered”.

“Do you like swimming in the sea, on holiday?” …   “Yes” was reply.

“This year, because of Covid, you need to get a holiday injection in your arm.  It doesn’t hurt and we’ve all had ours.”

“After 2 holiday injections, you’re ready for summer holidays.”

Bad news became good news.  Holidays … nice!

 

Children traveling without a covid Vaccine

In many cases children can travel without a covid vaccine, but you may need a PCR test before the trip out and the trip back.  You might well develop covid whilst you are abroad and then you are stuck.

A classmate of Monty was traveling with his vaccinated parents and the border policeman was not sure whether to let him through, since he had no PCR test, or vaccine certificate.

The Pfizer vaccine does look the best choice for a healthy 17-year-old.  For them, safety is more important than efficacy, because they are at almost zero risk from the current variants of the virus.  This may very well change in the coming years.

  

Covid risk for those with autism

Whether you are at elevated risk from Covid depends on what kind of autism you have.  I think my son is at even lower risk than his peers; he very rarely gets sick and another reason is his steroid inhaler for asthma; this actually reduces the chance of mild covid becoming severe covid.  Steroids are now widely used in hospital treatment, but really should be started before you even think about going to hospital.

People with MS (multiple sclerosis) taking disease modifying therapy may be another group who are protected from severe Covid.  These therapies block the cytokine storm that takes you from mild covid to severe covid.  The studies are somewhat contradictory, so you can believe whichever you want.   

The expensive drug Remdesivir, was approved as a therapy even though it has no effect on mortality, which makes you seriously wonder about its benefit.  Not surprisingly, the cheap oral steroid drug, Dexamethasone, substantially reduces mortality.

What happened to hydroxychloroquine (HCQ) and Didier Raoult, the French Professor who promoted it?  He still thinks he is right, even though great efforts were made to prove him wrong, including using data later shown to have been faked.

A recently published study looking at 28,759 adults with mild COVID 19 in Iran actually supports Raoult:

https://www.sciencedirect.com/science/article/pii/S1567576921002721

Early administration of HCQ reduced the odds of hospitalization by 38%.

Early administration of HCQ reduced the odds of death by 73%.

Serious HCQ adverse drug reactions were not reported in any of the age groups with or without comorbidities.

 

Does hydroxychloroquine have an anti-viral benefit in Covid-19?  Only you can decide.  The scare stories about dangerous side effects were evidently grossly overstated, which makes you wonder what else was made up by the naysayers.

I think this shows that you can find data to support whichever side you favour.  This seems to happen quite often, when a medical issue becomes politicized.

My own Covid therapy was hydroxychloroquine as the antiviral, to which I would have added prednisone if necessary.  As a local doctor told me, you do not want to go to hospital with Covid.

Back to autism.

Some types of autism are associated with comorbidities elsewhere in your body.  These can include problems with your lungs, as in the case of Down syndrome. If you have Prader Willi syndrome, you will present with autism and obesity.  The obesity is the covid risk.

Intellectual disability is put forward as a Covid risk, which makes sense.  People with ID/MR are likely to live in group homes or institutions, where they may be exposed to the virus and they may not follow all the protective measures.  People taking psychiatric drugs are likely to be overweight, which is a bigger risk factor than age.  People with ID/MR are likely to get worse healthcare than typical people, even when there is no health crisis.  The study below seems very credible'. 

After old age, intellectual disability is greatest risk factor for death from COVID-19, study finds

The results showed that those with intellectual disabilities were 2.5 times more likely to contract COVID-19, were about 2.7 times more likely to be admitted to the hospital and 5.9 times more likely to die from the infection than the general population.

Nowadays most people diagnosed with autism do not have any intellectual disability, so it makes sense that in some countries they have made people with intellectual disability, rather than just autism, as a priority group for vaccination.  

On a practical level, an overstretched hospital is not going to be a good place for an adult with intellectual disability, with or without autism.  They should indeed be prioritized for vaccination

When it comes to autism parents there seem to be three groups: -

1.     Desperate to get the vaccine

2.     Desperate to avoid the vaccine

3.     Desperate to go on holiday

 

 

 

 

Autism – Awareness and Acceptance

 

There is a lot of talk this month about autism awareness and acceptance.  Some people get very excited about this and some people get quite upset about it; it seems to depend on how old the person with autism is and how severely impaired, if at all, they are. 

For much of the confusion we have to thank the psychiatrists who keep broadening the definition of autism and their lack of using one of the standard ratings scales to tell people just how autistic they actually are (like on a scale of 1 to 100, not 1 to 3).  The result is a widespread misunderstanding of what the word autism means.  Nowadays it means very little.

I think that bubbles better represent autism than pieces of a puzzle.

People with any difference, from mild to severe, tend to live in their own little bubble; but bubbles do have a nasty habit of bursting and then a different reality may present itself. Also, if you live in a bubble you generally only hear people with similar opinions to your own – the social media echo chamber effect.

Monty, aged nearly 18, continues to live happily in his enchanted bubble. School is online currently, but hopefully back to normal again next week. Online school is pretty good because his assistant comes to our house.  Easter was celebrated and a couple of girls from his class came to hunt for chocolate eggs with him in our garden.

We visited some of Monty’s distant relatives who are usually looking after their grandson with severe non-verbal autism.  The boy has been out of school for a year, because his special school closed due to Covid.  He lives in a very different kind of bubble. Grandad was wondering where the boy will be in 10 years’ time, presuming it likely to be in an institution, a very different kind of bubble and not an attractive one.

On Sunday we were invited by friends for lunch beside the river. Their adult children do not come, likewise our adult son, they all have better things to do.  Monty was invited and we are beyond the stage where you would leave him at home, out of sight, with a babysitter. Our friends are aware that Monty has autism and they “accept it”, or else they would not invite him.

It is easy to accept a young man who sits nicely for two hours, eats his soup and then devours his fish, carefully avoiding the bones and a little later, asks what is for dessert.  He makes his own way to the restroom, we are not worried he will go the women’s rather than the men’s by mistake, or that he will run out of the building, or jump into the river. So, what is there not to accept?

Can you bring a non-verbal 11-year-old boy, with severe untreated autism and a very limited diet, to a two hour lunch in a busy restaurant, surrounded by people he does not know?  I don’t think so, it would not be accepted.

Even when Monty had quite challenging behaviors, when much younger, he did get taken everywhere.  Fortunately, small children can get away with a lot - we are programmed to be sympathetic and make allowances for them.  When children become more adult-like, we expect different behavior.  If your development plateaus at the level of a 2-year-old, strangers are going to want to keep their distance when you get bigger.

Rather than blame the strangers for their lack of tolerance, why not do more to ensure development does not stall at such an early age?  How about some awareness of that?

I keep asking why special schools where we live do not teach any alternative method of communication to non-verbal autistic children.  Schools for the deaf do teach sign language, but with a diagnosis of autism you are left with nothing.  No use is made of augmentative communication devices.  No use is made of the Picture Exchange Communication System (PECS).

Clearly awareness can be a first step towards acceptance, but there are limits to what people can accept.

My elder son told me about a boy in his circle who is very obviously gay and yet his father remains unaware, even his wife has not broken the news to him.  The news would not be well accepted, so it is just hidden away.

Now that most autism diagnosed is very mild, it is beginning to get drawn into the trending gender dysphoria topic.  Being autistic is being equated to being gay and just another difference to celebrate with rainbow colours.  It is put forward as something you can choose to mask, with your built-in cloaking device, if you want, but then you risk damaging your “mental health”.

Not surprisingly some parents of children with severe autism want a new descriptive word for their child’s condition. Autism has lost any clear meaning.  I guess they would love to buy one of those cloaking devices to mask their child’s autism, then they too could go for lunch at a fancy restaurant.

Among the least accepting adults I have met were parents at a musical performance put on by children with autism.  The parents made no allowances for interruptions made by younger siblings in the audience, it was a case of “remove your screaming child!”.  I assumed they would be more sympathetic than regular parents, but not at all.

The next question is whether acceptance is enough. At a recent parent teacher meeting at Monty's school, one new teacher was telling me how he identified with our situation, because his young niece has autism and some physical disability. He thought acceptance was the key issue at school and told me how well Monty is accepted by his class.  I did not disagree, but in my mind I was thinking "well actually, how about some learning?".  One advantage that Monty has developed since taking his PolyPill therapy, is that he has learnt many new skills that help to make him accepted.  He skis well, swims well, plays the piano well and is better at mathematics than many of his peers, so they know he is more than just a token autistic.  I think he earned some respect.  On the inclusion - delusion scale regarding mainstream schooling he is doing well.

 

What to do?

In some people’s bubbles, they are already doing a lot to improve their situation. These are the bubbles to be made aware of.

People tend to want to peer inside other people’s bubbles but then step back.  The author of a book on ECT (electro-convulsive therapy) to successfully treat her son’s severe self-injurious behavior (SIB), is bemused as to why other parents do not follow her example.  I told her that for most people ECT would be a step too far.

You would think there should be a basic standard of care available to all.  If the parents do not have a grip on the situation, at least the school should and ideally so should the pediatrician.  This probably does exist somewhere, perhaps in Scandinavia.

Acceptance has different aspects, of course it is good that people can accept others with differences and include them.  If parents just accept that their child is severely disabled by autism and then assume that nothing can be done, that would be really bad. Who ever did well by giving up?

As usual a lot of harm can be done with the best of intentions.  At both ends of the spectrum there are very one-sided views.  From the very severe end come the “horror stories” of their daily life and the conviction that there is an explosion in the incidence of their very severe autism.  At the ever-booming, slightly affected end of the spectrum is a small vocal group who are anti anything that can treat autism, whether it is behavioral therapy or pharmaceuticals. 

You might wonder what happens to all those neurodivergent people with Schizophrenia or Bipolar – don’t they get celebrated?  I do not see anyone lobbying for awareness and acceptance of them.  Why is that?  Too scary perhaps.

In many parts of the world the child with untreated severe autism is going to end up living in the same place as the adult diagnosed with Schizophrenia. Autism comes home to its big brothers Schizophrenia and indeed Bipolar, with all their overlapping miss-expressed genes.

Choose your bubble wisely.

 

What should be done?

The psychiatrists paid to write the diagnostic manuals (DSM5) need to step into the 21^st century and start doing the job properly.

An observation of autistic behaviors in a patient needs to be evaluated and graded, for example with the Childhood Autism Rating Scale (CARS).  If the child is below the threshold of 30, they should not be diagnosed with autism.  Yes, that means that the school does not get extra payments and indeed neither do the parents – this often is the desire behind a diagnosis.

The people who actually have an autism score above the threshold should be the focus of the autism budget.  The bigger their challenges, the more support they should get.

One in five school children have special education needs of one sort or another and these clearly should be addressed, but not by misdiagnosing some of them with autism.

People who have a genuine autism diagnosis, should then start a process of determining what are its biological foundations and what can be done to reduce the damaging consequences that led to seeking a medical diagnosis in the first place.

If there are no damaging consequences, how can this be a case worthy of a medical diagnosis?  It isn’t autism, perhaps it is sub-clinical autism.  It is likely quirky, nerdy, introvert, anxious or even gay (ouch!) etc - all perfectly normal traits.

 

What will be done?

Nothing.

Choose your bubble on that basis and make it as enchanted as you can.

 

GABRA5 - Too much, or too little in Autism and Down Syndrome?

 

It is easy to get things the wrong way round.

This applies to science and to some people getting dressed

 

Today’s post was prompted by a reader updating me about Roche’s autism drug RO7017773, which targets the alpha 5 sub-unit of GABA_A receptors, encoded by the gene GABRA5.

Enrollment opens in phase II study of RO-7017773 for autism spectrum disorder

A 12-Week Placebo-Controlled Study to Investigate the Efficacy, Safety, and Tolerability of RO7017773 in Participants Aged 15-45 Years With Autism Spectrum Disorder (ASD)

 

Some people with severe autism, or just plain old ID/MR, which has gone out of fashion as a diagnosis these days, struggle to dress themselves because they do not notice what is inside out, or back to front.  I recall reading a few years ago about one autism parent who started a clothing company to get round this problem.

 

ADAPTIVE CLOTHING with no front/back and reversible so cannot be inside out.

 

I must say that writing this blog I am often left wondering which way round things are.  Do we want an agonist or an antagonist, a positive allosteric modulator or a negative one.  Many times things do seem to work backwards.

If you follow the research you will see that researchers often get things mixed up, with one group trying one strategy and yet another group of Ivy league bright-sparks doing exactly the opposite. The Vasopressin research is a good example.

Are they dyslexic? Perhaps dyspraxic?

Today it is the turn of GABRA5: do we want to upregulate it, or downregulate it?

GABRA5 is the gene that encodes the alpha 5 sub-unit of GABAa receptors.

A few years ago, the drug firm Roche spent a lot of money developing a negative modulator of these receptors.  That did not work and Basmisanil  (developmental codes RG-1662 and RO5186582) was abandoned as a treatment to raise cognition in Down syndrome.

Roche are now trialing the opposite therapy, a positive allosteric modulator of alpha 5 sub-unit of GABAa receptors, this time to treat autism.

 

Targeting GABA to treat autism

GABA is an important neurotransmitter and it seems to be dysfunctional in many types of autism, as well as other neurological conditions.

Both the A-type and the B-type of GABA receptors can respond to treatment.

When it comes to the A-type, we can be very clever and target specific sub-units of the receptor to achieve different goals.

 

Each receptor is made up of two α subunits, two βs and one γ.

In humans, the possibilities are made up of :

·         six types of α subunits (GABRA1, GABRA2, GABRA3, GABRA4, GABRA5, GABRA6)

·         three βs (GABRB1, GABRB2, GABRB3)

·         three γs (GABRG1, GABRG2, GABRG3)

 

What is particularly interesting is that the make up these receptors is not fixed, it is changing all the time and you can influence it with therapy.

It looks like you might even be able to treat alcohol addiction by targeting one of the sub-units.

In the world of autism it is more anxiety and cognition that we are targeting, but some types of seizure may also be targeted.

In previous posts I identified alpha 3 (GABRA3)  and alpha 5 (GABRA5) as subunits that I felt were the interesting ones to improve cognition in autism.  Alpha 3 is the target of the low dose clonazepam therapy.

Alpha 5 also fits in with my experience of inflammation-induced reduction in cognitive function.

 

α5 GABAA Receptors Regulate Inflammation-Induced Impairment of Long-Term Potentiation 

these results show that α5GABA_A receptor activity increases during inflammation and that this increase is critical for inflammation-induced memory deficits.

 

We know that female hormones modulate subunit expression, today we see that oxytocin also does this. So, yet another possible effect of a little more oxytocin.

 

Oxytocin modulates GABA_AR subunits to confer neuroprotection in stroke in vitro

Before I forget, I should add that that the nootropic herb Bacopa affects GABRA5 (in rats):-

https://www.sciencedirect.com/science/article/pii/S0753332218383914

“BME (Bacopa monnieri) significantly reversed the down-regulated Gabra1, Gabra4, Gabra5 gene expression of GABAA receptors subunits”

 

The following paper has been published since I wrote my earlier posts on GABRA5 and is very thorough.

 

Neurobiology and Therapeutic Potential of α5-GABA Type A Receptors

α5 subunit containing GABA type A receptors (GABA_ARs) have long been an enigmatic receptor subtype of interest due to their specific brain distribution, unusual surface localization and key role in synaptic plasticity, cognition and memory. These receptors are uniquely positioned to sculpt both the developing and mature hippocampal circuitry due to high overall expression and a distinct peak within the critical synapse formation period during the second postnatal week. Unlike the majority of other GABA_ARs, they exhibit both receptor clustering at extrasynaptic sites via interactions with the radixin scaffold as well as synaptic sites via gephyrin, thus contributing respectively to tonic currents and synaptic GABAergic neurotransmission. α5 GABA_AR signaling can be altered in neurodevelopmental disorders including autism and mental retardation and by inflammation in CNS injury and disease. Due to the unique physiology and pharmacology of α5 GABA_ARs, drugs targeting these receptors are being developed and tested as treatments for neurodevelopmental disorders, depression, schizophrenia, and mild cognitive impairment. This review article focuses on advances in understanding how the α5 subunit contributes to GABA_AR neurobiology. In particular, I discuss both recent insights and remaining knowledge gaps for the functional role of these receptors, pathologies associated with α5 GABA_AR dysfunction, and the effects and potential therapeutic uses of α5 receptor subtype targeted drugs.

 

Genetic Disorders with Altered α5 GABA_AR Neurotransmission

While acute reduction in α5 GABA_ARs has shown potential for improving cognition and memory, further studies both in mouse models and human patients link long term reduction with significant pathologies. Reduced α5 GABA_AR levels, function or protein interactions have been observed in patients with neurodevelopmental disorders including intellectual disability, epilepsy and autism. Common conditions among these disorders include cognitive impairments, increased anxiety, autism-related behaviors, sleep disorders and epilepsy susceptibility

 

α5 GABA_AR Therapeutics

NAMs that selectively reduce α5 GABA_AR function have been heavily pursued for the potential development of cognitive enhancing or “smart” drugs. The following are a selection of α5 GABA_AR NAMs: L-655,708, α5IA, Ro15-4513, MRK-016, RO4938581, and RY-80 Importantly, α5 NAMs did not exhibit the convulsant or pro-convulsant activity of more general alpha subunit NAMs, had good oral bioavailability and easily crossed the blood brain barrierIn contrast to NAMs which act via the GABA_AR benzodiazepine binding site, S44819 was recently identified as a competitive antagonist of GABA at α5 GABA_AR and showed similar pro-cognitive effects as NAMs: blocking α5-GABA_AR tonic current, enhancing LTP, reversing scopolamine-induced impairment of spatial working memory and enhancing object recognition memory). Finally, recent evidence for beneficial effects of positive allosteric modulators (PAMs) in aged brain cognition, autism, depression and schizophrenia has bolstered α5 PAM drug development. A selection of α5 preferring PAMs includes SH-053-R-CH3-2′F, MP-III-022, and GL-II-73. Potential therapeutic applications for α5 preferring NAMs and PAMs are discussed below with a focus on CNS specific uses (Table 1).

 

NAM α5 GABA_AR Therapeutic Applications

Pro-cognition

Developmental Disorders

Although these pharmacological successes led to a Phase II clinical trial for a related compound RG1662 (Hoffman-La Roche) in Down syndrome patients, the trial did not meet the primary and secondary endpoints of improved cognition and function.

Inflammation Induced Mild Cognitive Impairment and Post Anesthesia Memory Blockade

 

 

PAM α5 GABA_AR Therapeutic Applications

Neurodevelopmental Disorders

Mouse models of neurodevelopmental disorders that present with insufficient inhibitory tone show improvement with positive modulators of GABA_AR signaling. In the Scn1a+/− mouse model of Dravet syndrome, a severe childhood epileptic encephalopathy syndrome with hyperactivity and autism behaviors, abnormal social behaviors and fear memory deficits were rescued following treatment with a benzodiazepine, clonazepam. In an ASD mouse model with reduced GABA_AR-mediated inhibition, the BTBR T+tf/J mouse, the α2,3 and 5 PAM L-838,417, improved deficits in social interaction, repetitive behaviors, and spatial learning.

 

Mild Cognitive Impairment in Aging

Although α5 GABA_AR NAMs enhance memory in young rodents, it appears positive modulation may be more therapeutic in aging brains impaired by excess activity. Particularly in disorders such as Alzheimer’s which are hallmarked by overexcitation 

 

Depression and Schizophrenia

Another important unmet need where α5 GABA_ARs PAM pharmacotherapy may be applicable is in the development of new fast-acting anti-depressant drugs

  

 

Roche

Roche did develop a (NAM) drug to target the alpha 5 sub-unit in order to improve cognition in Down Syndrome. 

 

The GABA _A α5-selective Modulator, RO4938581, Rescues Protein Anomalies in the Ts65Dn Mouse Model of Down Syndrome

 

RG1662, a Selective GABAA α5 Receptor Negative Allosteric Modulator, Increases Gamma Power in Young Adults with Down Syndrome.

 

Basmisanil ( RG-1662 and RO5186582) is a highly selective inverse agonist/negative allosteric modulator of α₅ subunit-containing GABA_A receptors which is under development by Roche for the treatment of cognitive impairment associated with Down syndrome. As of June 2016, it is no longer studied.

 

Then came the opposite strategy, a PAM (positive allosteric modulator):-

 

RG 7816

Alternative Names: RG-7816; RO-7017773

 

Mechanism of Action  GABA A alpha 5 receptor modulators

Orphan Drug Status  No

New Molecular Entity  Yes

Highest Development Phases

Phase II  Pervasive child development disorders

Most Recent Events

·         23 Feb 2021Phase-II clinical trials in Pervasive child development disorders (In adolescents, In adults) in Canada (PO) (NCT04299464)

·         12 Mar 2020Hoffmann-La Roche plans a phase II trial for Pervasive child development disorders (Autism Spectrum Disorder) in USA (PO) (NCT04299464) (EudraCT2019-003524-20)

·         22 Apr 2019Roche completes a phase I trial in Pervasive child development disorders (In volunteers) in USA (PO, Capsule, Tablet) (NCT03847987)

 

RG7816 GABA-Aa5 PAM

autism spectrum disorder

4. Phase 1

Description/Summary:

RG7816 is a small molecule highly selective positive allosteric modulator of the GABAA α5 receptor, which is expressed in key brain regions for autism spectrum disorder. Two phase I clinical trial is evaluating RG7816 for the treatment of patients with autism spectrum disorder.

 

Conclusion

Modifying the response specific to sub-units of GABA_A receptors is a really nuanced therapy.

In a way I am not surprised that there is, as yet, no one size fits all therapy.

Will Roche’s trial of a drug to increase the effect of GABRA5 (a PAM) be more successful than their drug to reduce the effect of GABRA5 a (NAM)?

I do not know, but in the perfect world you would have both drugs and then see if fine-tuning GABRA5 ( + or -), on a case by case basis, was therapeutic. That would be personalized medicine.

At least we can modify GABRA3 extremely cheaply with Professor Catterall’s low dose clonazepam.

Note that we saw in my original posts that the Japanese attribute the benefit of low dose clonazepam to the γ2 subunit of GABAa receptors, which is encoded by GABRG2, for those who don’t speak Greek.

 

PX-RICS-deficient mice mimic autism spectrum disorder in Jacobsen syndrome through impaired GABAA receptor trafficking  

A curative effect of clonazepam on autistic-like behaviour

 

These results demonstrate that ASD-like behaviour in PX-RICS^−/− mice is caused by impaired postsynaptic GABA signalling and that GABA_AR agonists have the potential to treat ASD-like behaviour in JBS patients and possibly non-syndromic ASD individuals.

 

Jacobsen syndrome is a condition mainly found in girls and it is one of those more rare small-headed conditions (microcephaly). It features MR/ID and often an autism diagnosis.  It is caused by missing part of chromosome 11, apparently one of the most disease-rich chromosomes.

The fact that low-dose (sub-anxiolytic) clonazepam rescued the autistic behavior in mice does not mean that anyone has tried it in little girls with Jacobsen syndrome; that would require too much common sense.