SIGMAR1 Agonists – Therapeutic Swiss Army Knives $AVXL, Prilenia Therapeutics, $ATHA, $ALKS, $SAVA

SIGMAR1 Agonists – Therapeutic Swiss Army Knives

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My intention is to call on a paper which unravels the mystery of mechanism of action of the SIGMAR1 receptor agonists, among them is Blarcamesine ($AVXL) and Pridopidine from Prilenia Therapeutics Development LTD.

The paper in question is titled

[1] Sigma-1 Receptor (S1R) Interaction with Cholesterol: Mechanisms of S1R Activation and Its Role in Neurodegenerative Diseases

Vladimir Zhemkov 1, Michal Geva 2, Michael R. Hayden 2,3 and Ilya Bezprozvanny 1,4

Link https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071319/

The abstruct reads..

Abstract: The sigma-1 receptor (S1R) is a 223 amino acid-long transmembrane endoplasmic reticulum

(ER) protein. The S1R modulates the activity of multiple effector proteins, but its signaling

functions are poorly understood. S1R is associated with cholesterol, and in our recent studies we

demonstrated that S1R association with cholesterol induces the formation of S1R clusters. We propose

that these S1R-cholesterol interactions enable the formation of cholesterol-enriched microdomains in

the ER membrane. We hypothesize that a number of secreted and signaling proteins are recruited

and retained in these microdomains. This hypothesis is consistent with the results of an unbiased

screen for S1R-interacting partners, which we performed using the engineered ascorbate peroxidase

2 (APEX2) technology. We further propose that S1R agonists enable the disassembly of these

cholesterol-enriched microdomains and the release of accumulated proteins such as ion channels,

signaling receptors, and trophic factors from the ER. This hypothesis may explain the pleiotropic

signaling functions of the S1R, consistent with previously observed effects of S1R agonists in various

experimental systems.

The SIGMAR1 receptors are in this paper associated with parts of Endoplasmic Reticulum which contain the ER/Mitochondria-Associated Membrane (MAM). Yet these are not the only places which hold SIGMAR1 receptors, to present evidence that SIGMAR1 receptors are also involved with the Nucleus Envelope, I am going to quote the abstruct from another paper.

The sigma-1 receptor (Sig-1R) chaperone at the endoplasmic reticulum

(ER) plays important roles in cellular regulation. Here we

found a new function of Sig-1R, in that it translocates from the ER to

the nuclear envelope (NE) to recruit chromatin-remodeling molecules

and regulate the gene transcription thereof. Sig-1Rs mainly reside at

the ER–mitochondrion interface. However, on stimulation by agonists

such as cocaine, Sig-1Rs translocate from ER to the NE, where Sig-1Rs

bind NE protein emerin and recruit chromatin-remodeling molecules,

including lamin A/C, barrier-to-autointegration factor (BAF), and histone

deacetylase (HDAC), to form a complex with the gene repressor

specific protein 3 (Sp3). Knockdown of Sig-1Rs attenuates the complex

formation. Cocaine was found to suppress the gene expression

of monoamine oxidase B (MAOB) in the brain of wild-type but not

Sig-1R knockout mouse. A single dose of cocaine (20 mg/kg) in rats

suppresses the level of MAOB at nuclear accumbens without affecting

the level of dopamine transporter. Daily injections of cocaine in

rats caused behavioral sensitization. Withdrawal from cocaine in

cocaine-sensitized rats induced an apparent time-dependent rebound

of theMAOB protein level to about 200% over control on day 14 after

withdrawal. Treatment of cocaine-withdrawn rats with the MAOB

inhibitor deprenyl completely alleviated the behavioral sensitization

to cocaine. Our results demonstrate a role of Sig-1R in transcriptional

regulation and suggest cocaine may work through this newly discovered

genomic action to achieve its addictive action. Results also

suggest theMAOB inhibitor deprenyl as a therapeutic agent to block

certain actions of cocaine during withdrawal.

Title of the paper:

[2] Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatinremodeling factors at the nuclear envelope

Shang-Yi A. Tsaia,1, Jian-Ying Chuanga,b,1, Meng-Shan Tsaia, Xiao-fei Wangc, Zheng-Xiong Xic, Jan-Jong Hungd,

Wen-Chang Change, Antonello Boncif,g,h, and Tsung-Ping Sua,2

LINK: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4664336/ kjinm

SIGMAR1 Agonists and ER/MAM Microdomains

To have a better look at these papers is to recognize that different neurodegenerative diseases have been traced to the terms of health of SIGMAR1 receptors. Since it is impossible for me to read that many papers, and it would require to posses tremendous amount of knowledge and high level of analysis so instead I rely here on [1]. The paper has two officers of Prilenia Therapeutics LTD as co-authors.

This is further supported by human genetic studies, showing that complete loss of function (LOF) mutations in the S1R are associated with a juvenile form of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD), while partial LOF mutations cause late onset ALS [11–14]. Thus, there is a gene dosage relationship between S1R activity and the age of onset of ALS with the complete loss of S1R associated with the earliest age of onset. Additional LOF mutations in the S1R cause distal hereditary motor neuropathies (dHMN) [15–19]. Furthermore, S1R expression levels are reduced in sporadic ALS [20], Parkinson’s disease (PD), and Alzheimer’s disease (AD) patients [21,22].

This connection is very important since the health of SIGMAR1 would be then bestowing a natural resistance against these ailments as I intepret the implcations correcetly, here. When talking SIGMAR1 health we can as well talk quality and quantity. Quality can be traced to mutation in the SIGMAR1 gene and quantity into relative amount of trascribed protein. I believe that at this point both of these can be measured for truely precision medicine. SIGMAR1 agonist release into CNS tissues proteins which shortage can be blamed on the SIGMAR1 condition or lack of in quantitative sense. This pictutre might be partialy true or might be very strong, but the true strength will be revealed in number of trials where SIGMAR1 agonist will be given to the patients. If indeed SIGMAR1 gene expression can be linked to neurodengenerative diseases then a genetic tests can be administered to assess the probability of an individual to succumb to any of these ailments, at least in the very general terms. Nevertheless, if such connection can be drawn then purely “natural” way has been found to ameliorated conditions leading to these diseases. I listened to presentation by Prilenia officer, available on Prilenia’s website, and again I heard a notion implying that the drug is more of a preventative so that it should be given and is most effective in patient at the earliest onset of the symptoms and the disease than at the more advanced stages. As notion has been expresed by both, $AVXL and Prilenia, it seems to confirm what I wrote above.

In paper [1] the ER/MAM microdomains are involved in “processing” post transciption proteins into fully folded functional ones, but these microdomain are used also as “storage facilities’ for those protein. The scientist involved just advanced this hypothesis in this paper. The number of the protein has been “captured” and their connections to various physiological mechanism vaugely given. They range from Ca+2 channel regulating to extracellular matrix protein. The spread in function between those protein covers many of those therapeutic targets advanced by various companies. In few cases, these companies have been mentioned on this blog. For example, $ATHA Athira has been talked about in terms of the merits of its terapeutic target which is a neural growth factor not unsimilar to brain derived neurotrophic factor (BDNF) released by SIGMAR1 agonists. If indeed the SIGMAR1 agonist action releases plethora of vital to neural (and not only neural) health factors then most of these companies are concentrating on a single factor in the CNS health puzzle of tens if not hundreds of factors. The CNS diseases are then attacked on the perifery leading to limited results vs. serendipitously hitting the jackpot.

The above paper also stated that the action of the agonists releases the SIGMAR1 protein into the endoplasm. The seccond of the papers [2] places the next position where the SIGMAR1 protein ends up after this process as the Nuclear Envelope. The paper [2] contains a text box titled Significance.

That is only part of the story. a company called Alkermes $ALKS works on compound bringing about increased trascription of genes connected with the creation of synapses. The macropicture of that interaction can be presented with the slide from the corporate presentation 2021.

Cocaine apparently increased the levels of Sig-1R, lamin A/C, and emerin (Fig. 2H). Those binding to HDAC3 (24). To clarify whether emerin also binds with other class I HDACs, we performed co-IP assays for emerin, HDAC1, and HDAC2. Anti-emerin antibody pulled down both HDAC1 and HDAC2 (SI Appendix, Fig. S5A). Conversely, the HDAC2 antibody pulled down emerin and HDAC1 (SI Appendix, Fig. S5B). Those results indicated that emerin interacts with HDAC1 and HDAC2, as well as with the recently reported HDAC3. Cocaine dose-dependently increased the interaction of emerin with both HDAC1 (SI Appendix, Fig. S5C) and HDAC2 (SI Appendix, Fig. S5D).

The interacting proteins are the same but the resulting changes are different. Cocain blocks the production MAOB protein which is plays a role in controlling the quantity of Dopamine the feel good neurotransmitter. The user of cocaine have elevated levels of Dopamine. Upon break in usage he feels withdrawal symptoms as MAOB surges to 2-5 fold greater amount cutting the available Dopanime. The mechanism involves the same proteins but the inner workings are still a mystery. Each SIGMAR1 agonist will have smoehow different pattern of action, at least what the current knowledge suggests. Ultimately, there will be a race between all those pictured on the opening illustration. $AVXL and Prilenia are at the best runners at this moment. Their piplines are not conflicted at this moment as Prilenia pursuits ALS and Huntington Disease, but soon will try its drug on Rett Syndrome, in few years time. At this point Prilenia is private.

Paper [1] ishas been written as an extesion of Prilenia Theurapeutics LTD study. As far I know at this moment both Blarcamesine and Pridopidine are the most advanced in clinical studies SIGMAR1 agonist. Paper [1] makes a mention of it.

Recent clinical studies have shown the potential efficacy of the selective S1R agonist

pridopidine in HD patients, demonstrating maintenance or slowing the decline of

the patient’s functional capacity [127,128]. The non-selective S1R/Muscarinic (M1R) agonist

blarcamesine shows a potential beneficial effect in AD [129]. Clinical pivotal studies

with pridopidine are currently ongoing for HD and ALS (NCT04556656, NCT04297683).

Blarcamesine is currently being evaluated for AD, Rett syndrome, and PD dementia patients

(NCT04314934, NCT04304482, NCT04575259). Results of completed clinical trials

of S1R agonists in variety of disorders have been comprehensively summarized in recent

reviews [4,130].

Number of voices has been clamoring to speed up the development of Blarcamesine. Prilenia has targeted as its first dieases to tackle Huntington Disease. It phase 2 has interestigly stretched into 5 years of data in OLE study, not unsimilar to Blarcamesine AD phase 2 OLE.

Before I wraped up this post I would like to call on a third paper

[3] Stimulation of astrocytic sigma-1 receptor is sufficient to ameliorate inflammation- induced depression

Author links open overlay panelLinGuo^ab1TianyuGao^a1CeGao^aXiaoxiaJia^aJingNi^aChaojunHan^cYunWang^a

Quoting the abstruct from the paer [3]

Astrocytes play important roles in the development of depression. As a promising target for antidepressant development, sigma-1 receptor (Sig-1R) is reported to promote activation of astrocyte in chronic stress-induced depression in our previous study. However, astrocytes are hyper-activated in inflammation-induced depression, raising concerns of whether stimulation of astrocytic Sig-1R would exert antidepressant-like effect in inflammation-induced depression. Here we reported that specific stimulation of astrocytic Sig-1R using adeno-associated virus (AAV) significantly attenuated lipopolysaccharide (LPS)- induced depressive-like behavior in the forced swim test (FST), tail suspension test (TST), sucrose preference test, and improved the memory function in novel object recognition test. Besides, specific stimulation of astrocytic Sig-1R decreased the activation of astrocyte and microglia, as well as increased brain-derived neurotrophic factor (BDNF) in LPS-induced depression. In primary cultured astrocytes, overexpression of Sig-1R also reduced the expression of IL-1β, TNF-α, iNOS during inflammation-treated astrocyte. Taken together, the results suggest that specific stimulation of astrocytic Sig-1R ameliorates inflammation-induced depressive-like behavior, providing the evidence that astrocytic Sig-1R could represent a reliable therapeutic target for depression.

Though, the paper [3] deals with inflammation caused depression it references the lowering of inflammation biomarkers among astrocytes. These cells nurture the neuron and inflammation is mentioned as a cause of neurodegeneration by few companies in their narratives of providing therapeutic action. To mind comes here $SAVA. here, again we are looking at very broad therapeutic action of SIGMAR1 agonists vs. single or double target from its competitors. The middling results from $SAVA, between total losers like $BIIB Aducanumab and promissing high fliers like $AVXL, are proof that $SAVA laboring under the single or double therapeutic target syndrome.

The scientific evidence is piling up when it comes to MOA of SIGMAR1 agonists. FDA does not like MOA missing from the clear picture but this is quickly changing as researchers have taken their interest to SIGMAR1 receptors. This field is vast and barely scratched so chances for seminal papers are great and I hope that money will not only flow from companies pursuing drugs but government grants on basic research.

CRISPIR has all the attension but as CRISPIR can cure those who have genetic mutations, it can not affect the kind CNS degeneration described in my post ( link:) https://piotrpeterblog.com/2021/03/05/novel-etiology-of-alzheimers-linked-to-neuronal-loss-of-function-due-to-changes-in-cellular-transcription-mechanism-and-dna-chromatin-complex-avxl-sava-atha-biib/ . The number of people with genetic disorders can be large so does the number of people with CNS degenerative diseases who carry no genetic mutation but succumb to age related degeneration. In public eye the amyloid plaque is the main actor behind Alzheimer’s degeneration. Yet, the cure can come from the proverbial left field on which we can find SIGMAR1 receptors. But unfortunaletly, this is not yet the case with the public. Patience is advised.