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.