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Showing posts with label Roche. Show all posts
Showing posts with label Roche. Show all posts

Tuesday 6 April 2021

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 GABAA 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 (GABRA1GABRA2GABRA3GABRA4GABRA5GABRA6)

·         three βs (GABRB1GABRB2GABRB3)

·         three γs (GABRG1GABRG2GABRG3)

 

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 α5GABAA 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 GABAAR 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 Gabra1Gabra4Gabra5 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 (GABAARs) 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 GABAARs, 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 GABAAR 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 GABAARs, 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 GABAAR neurobiology. In particular, I discuss both recent insights and remaining knowledge gaps for the functional role of these receptors, pathologies associated with α5 GABAAR dysfunction, and the effects and potential therapeutic uses of α5 receptor subtype targeted drugs.

 

Genetic Disorders with Altered α5 GABAAR Neurotransmission

While acute reduction in α5 GABAARs 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 GABAAR 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 GABAAR Therapeutics

NAMs that selectively reduce α5 GABAAR function have been heavily pursued for the potential development of cognitive enhancing or “smart” drugs. The following are a selection of α5 GABAAR 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 GABAAR benzodiazepine binding site, S44819 was recently identified as a competitive antagonist of GABA at α5 GABAAR and showed similar pro-cognitive effects as NAMs: blocking α5-GABAAR 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 GABAAR 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 GABAAR Therapeutic Applications

Neurodevelopmental Disorders

Mouse models of neurodevelopmental disorders that present with insufficient inhibitory tone show improvement with positive modulators of GABAAR 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 GABAAR-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 GABAAR 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 GABAARs 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 GABAA 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 GABAA 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 GABAAR 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.






Wednesday 27 November 2013

Autism Clinical Trials, Arbaclofen (STX209), Curemark CM-AT and the Clever Chiropractor


 
In the world of clinical trials for drugs, judging success and failure can be highly subjective.  They try to make it as logical as possible and the method works pretty well for assessing things that you can measure objectively.




Primary and Secondary Endpoints
To quote Pfizer:

A trial endpoint of a clinical trial should fulfill three criteria: (1) be measurable and interpretable, (2) sensitive to the objective of the trial, and (3) clinically relevant. The endpoint can be either clinical or surrogate in nature.
If you are developing a drug to lower cholesterol or to increase survivability after a traumatic brain injury, it is pretty easy to define your endpoints.

When it comes to autism, one of the major hurdles is to define objective measurable endpoints.  As it stands today, none of the assessment tools are really fit for purpose, when Big Pharma is supposed to come along and invest hundreds of millions of dollars in some bright spark’s idea.

Arbaclofen, Seaside Pharma & Roche
The Swiss giant, Roche, recently had just such a problem.  They had partnered with a spinout company from MIT called Seaside Therapeutics.  One of the projects was to complete the trials of a fragile X targeted drug, called Arbaclofen (STX209).  During the 4+ years of trials Seaside had changed the primary endpoint.  Arbaclofen started out as drug to treat one aspect of behaviour, but by the time they got to phase 3  clinical trials this had been changed to lethargy and social withdrawal scores from the Autism Behavior Checklist (ABC).
Quite logically, Roche assessed the result of the stage 3 trial against its primary endpoint.  Based on the total cohort in the trial, Roche determined the drug to be a failure and pulled the plug on financing the drug further.
The owner and developer of the drug, Seaside, even though they have recently raised $90 million, said they could no longer continue to fund the trial and all those kids in the trial would have to be weaned of Arbaclofen ASAP.
It turns out that among the families involved in the trial there were many reports of wonderful improvements on Arbaclofen.  They even formed a group to lobby for a continuation of the trial.  There website is interesting.
It now appears that Seaside has had a rethink and will try again with a new trial with a new primary endpoint (mark 3).

Background on Arbaclofen
Some of the first studies of Arbaclofen were conducted in patients with Fragile X syndrome, a genetic condition caused by a change in a gene called FMR1, which normally is needed to make the brain grow properly. Fragile X is the most common form of inherited intellectual disability in boys and can be a cause of autism or related disorders. In those Phase 2 trials, Arbaclofen was shown to decrease social withdrawal and improve adaptive social function.

A  Phase 2a study conducted at 8 sites and involving 32 children showed significant positive behavioral outcomes, including improved scores on the Aberrant Behavior Checklist-Irritability Score (ABC-I) and on the ABC-Social Withdrawal Scale. The most common adverse events were agitation, irritability, fatigue, psychomotor hyperactivity, insomnia and diarrhea. Most resolved without dose changes, but one serious adverse effect did occur during down-titration of the medication.
In July 2011, Seaside Therapeutics, announced that 25 sites across the nation will be involved in a new clinical trial to involve approximately 150 ASD patients between the ages of 5 and 21.
STX209 is an orally-administered GABA-B agonist; the drug acts by stimulating the release of GABA, a neurotransmitter in the central nervous system. GABA inhibits the release of glutamate, an excitatory neurotransmitter, for which an overabundance negatively affects the ability of neurons to communicate with each other.

The GABA "A" receptor, is a chloride channel, while STX209 targets the GABA "B" receptor, which is a G-protein coupled receptor and regulates a different set of molecules from GABA "A".

The original basis for starting this blog was my success with bumetanide, which is affecting the GABA “A” receptor.  In the brain, bumetanide blocks the NKCC1 cation-chloride co-transporter and thus decreases internal chloride concentration in neurons.


Medicine as an art and a science
Mark Bear is a neuroscientist at MIT and he was the co-founder of Seaside Therapeutics.  He is clearly a very brainy guy.
There is a derivative of his Arbaclofen called Arbaclofen Placarbil.  I found it interesting that this substance was also being trialed as a therapy for Multiple Sclerosis and GERD.  GERD is the medical term for heartburn/indigestion.
Incidentally, Arbaclofen Placarbil failed both trials.


Now to the Clever Chiropractor and her Pancreatic Enzymes
People outside the US will find it very strange that in the US chiropractors and osteopaths have the same right to prescribe drugs as conventional medical doctors. 

Outside of the US, if you want to be a doctor you have to apply to medical school and in most countries the competition is very tough. There is no plan B if your exam grades slip.  In the US it is different, if your grades and resources are not taking you to the Harvard, you can opt to become an osteopathic physician or a chiropractic physician.
Rather than Harvard or MIT, Joan Fallon trained as a chiropractor at Palmer University.

Not surprisingly the scientific community is skeptical of her autism treatment, which is linked to pancreatic enzymes.  After all, how can a chiropractor know more than Ivy League neuroscientists?

Peter, on the other hand, thinks that Fallon is actually far more savvy than the very brainy people over at Seaside.  Her therapy may, or may not be effective, but her method of developing it is highly effective.
First she raised $6 million to start her company Curemark, then as trials progressed she very recently she raised another $18 million.
The reason I like what Fallon is doing is that she has figured out which sub-type of autism is helped by her therapy and she has identified a bio-marker for that subgroup.


Hallelujah, a street-smart autism researcher !
If you want to enroll in a clinical trial for Curemark’s CM-AT, first they will screen out the 50% that do not have the biomarker.  Fallon is making sure that her clinical trial results look as good as possible, by only including those subjects most likely to benefit.  This may sound like common sense, but in autism research this is a revolution.

CM-AT therapy and the biomarker
The reason the autism world are skeptical of Fallon, is that she is going on about Secretin and pancreatic enzymes.
Many years ago parents thought that Secretin was going to be the wonder cure for autism; it turned out not to be.  By reading her patents, it is clear that Fallon has some faith in the role of secretin, in addition to enzymes produced in the pancreas.

What impressed me was how she has screened the kids allowed into her clinical trials.


Eligibility
·         Inclusion criteria:
o    Child is 3-8 years old
o    Child has a diagnosis of autistic disorder
o    Child must have a low fecal chymotrypsin level (we will measure)

·         Exclusion criteria:
o    Child must have no dietary restrictions (other than for a nut allergy)
o    Child may not have an allergy to pork products
o    Child may not have a history of severe head trauma or stroke
o    Child may not have had a seizure within the past year
o    Child may not be diagnosed with: HIV, cerebral palsy, endocrine disorder or pancreatic disease
o    Child may not be taking any enzyme product, amino acids, secretin product or stimulant medication currently 

Low fecal chymotrypsin level” is a standard lab test available all around the world.  Over the years Fallon has found that it is a biomarker of the kids who benefit from her patented mix of enzymes sprinkled on their meals.
You actually can buy a very similar product called Creon, or Kreon, depending on which country you live in.  The reason why you cannot be in the trial if you have a pork allergy, is that they use the pancreas of dead pigs to make the enzymes.  This is bad news if you are Jewish, Muslim, a Seventh Day Adventist, or indeed the pig.

The active ingredient in Creon is Pancreatin. Pancreatin contains the pancreatic enzymes lipase, amylase and protease. These assist the digestion of fat, carbohydrates and proteins.

Update on trials of CM-AT
Here is a link to the always-helpful Simons Foundation, with the expected skeptical comments from experts:-

 https://sfari.org/news-and-opinion/news/2010/first-drug-for-autism-enters-final-stage-of-testing

Now Curemark have finished there phase 3 trial, and guess what? It met both primary and secondary endpoints and has been “fast-tracked” by the FDA.

Congratulations Joan !!!
One of the secrets of her success was to have the good sense to enroll herself in a course on clinical investigation run by Harvard/Massachusetts general hospital.
 
Curemark Begins NDA Submission for CM-AT Autism Treatment
CM-AT had previously been granted Fast Track status by the FDA, a designation given to drug candidates that treat serious or life-threatening conditions and demonstrate the potential to address unmet medical needs. The rolling submission process allows companies with a Fast Track designation to submit the NDA in sections to the FDA as they are completed.
“Initiating our ‘rolling NDA’ submission is a major step in the registration process for CM-AT,” said Dr. Joan Fallon, Curemark founder and CEO. “We have an extraordinary opportunity to help many children with autism improve the quality of their lives and we will continue to work closely with the FDA to make that happen.”
Curemark previously announced the successful completion of its Phase III multicenter clinical trial of CM-AT for autism. CM-AT met both primary and secondary endpoints in its double-blind, randomized, placebo-controlled study of children with autism at 3 to 8 years of age.



  
Conclusion

I would suggest those researchers who believe that diet can be an effective therapy in sub-types of ASD take good note of Joan Fallon's methods. You might indeed be right, but unless you can prove it, the skeptics will always hold sway.