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THE $10 BILLION UNICORN IN INMUNE BIO: IT’S THE (MICRO)GLIA, STUPID!


Summary:

· The detrimental action of glia, mostly microglia, in the inflamed brain is the last piece of the scientific puzzle;

· We know XPro targets glial activity by focusing on reducing neuroinflammation;

· By reducing neuroinflammation, XPro effectively appears to revert glial activity back to its normal, caring, state;

· That the right microglial targeting leads to the right downstream effects has meanwhile been proven by more than one company;

· Opportunity lies in the fact that investors are still ignoring that proof, and are not fully appreciating the significance of INmune's success with clinically validated biomarkers.


Glial cells are red hot

The 1198-pages thick abstracts of the most recent Alzheimer’s/Parkinson’s conference 2022 mention ‘glia’ 763 times, of which ‘microglia’/’microglial’ 639 times. That’s almost as much as amyloid, the first hallmark of disease, is mentioned in these abstracts (907 times).

Glia'' is mentioned more than twice the number of times the word ‘inflammation’ is even mentioned in these same abstracts, and inflammation is the third hallmark of Alzheimer’s disease. So, apparently, innovation in AD/PD is focusing fully on glia. Yet, the average investor is pretty much ignorant about them. Neurodegenerative research these days is all about two types of glial cells: microglia mostly, and astrocytes to a lesser extent. This blog serves to provide insight as to why that is.


What are these glia, or glial cells?

Glia are non-neuronal immune cells in the central and peripheral nervous system, and include, astrocytes, oligodendrocytes, microglia, and ependymal cells. As immune cells, their function is among others to respond to invaders and to clean up debris. Yet, recent years have led to the equally important discovery that they are essentially permanent co-creators and sculptors of the brain by maintaining homeostasis, forming myelin and providing constant support and protection for neurons, if they are working well. Without them constantly working how they should, our brains would not thrive as they should.


How many are there?

Although differing views seem to exist on their exact numbers and proportionate relationship to the amount of neurons in the human brain, the number of glial cells is also astoundingly high. The human brain has an estimated 170 billion cells,half of which are estimated to be neurons. The number of glial cells seems to vary highly from one brain region to another and exact proportions aren’t clear, some articles and textbooks have quoted a 10:1 proportion in certain regios, with 10 being the amount of glial cells and 1 being the amount of neurons, but more recently, a proportion of 1:1 overall in the brain seems more likely. Yet, the amount of glia seems to drastically differ from one brain region to another, with some saying that glia are peaking in white matter at a 15:1 ratio, whereas in the very neuron-dense cerebellum, they only seem to exist in rather low numbers. Those numbers are quite dazzling; it basically means that, in some regions of the human brain such as white matter, the number of immune cells outnumbers the number of neurons, and not just a bit. Gray matter is largely made up of the unmyelinated parts of neurons—neurons that are not sheathed by glial cells—whereas white matter is comprised of axons wrapped in insulating oligodendrocytes. Or in other words: there may be more cells responsible for sculpting, maintenance and repair in those brain regions than cells providing actual function.


Zooming in on microglia

There are different types of glia in the humain brain. Astrocytes are the most abundant glial cells in the human brain (45-75%), then follow oligodendrocytes (19-40%), and then come microglia (10% or less), although again, these percentages vary from one publication to another, some publications even mentioning microglia may account for up to 20%.

The name says it already, the latter – microglia - are tiny. Their extensive caring and sculpting functions have been discovered in large part by the researchers from the team of Beth Stevens, a neuroscientist and associate professor in the Department of Neurology at Harvard Medical School and Associate Professor of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, who is also the director of the Stevens Lab, a neurobiology research laboratory at the Broad Institute of MIT and Harvard.


Source: http://brain.harvard.edu/?people=beth-stevens


Microglia are essential in neuronal and synapse development, and refinement or pruning, circuitry modeling, myelination and myelination repair. They remove excess synapses, neurons and debris to essentially sculpt and maintain the brain, thereby acting as the resident phagocytes in the brain. They are the brain’s first responders, and also crosstalk to astrocytes, leading the astrocytes to express neurotoxic activity.


Alector has a nice drawing showing their essential activities:



Source: Alector corporate presentation


The Janus-face of microglia

Here’s the tricky thing; when the essential repairmen and architects of our brains are surrounded by too much inflammation, they go haywire, start firing off inflammatory cytokines themselves, and destroy more than they repair. And it may not be in the neuroinflammation as such, but in that out of control behavior of our microglia, that mainly lies the neurodegenerative disease.

Since some years, scientists have started differentiating between two states, or phenotypes, of microglia, an M2 phenotype which is the normal caring one, and an M1 phenotype which is the damaging one. Some literature considers that in reality, the polarization between M2 and M1 is more of a gray scale. But with the aim of keeping it simple, I focus here on a 2022 article in Frontiers in Aging Neuroscience entitled ‘Microglia Polarization From M1 to M2 in Neurodegenerative Diseases’, which provides good info on these two phenotypes and what drives them:

Microglia-mediated neuroinflammation is a common feature of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Microglia can be categorized into two opposite types: classical (M1) or alternative (M2), though there’s a continuum of different intermediate phenotypes between M1 and M2, and microglia can transit from one phenotype to another. M1 microglia release inflammatory mediators and induce inflammation and neurotoxicity, while M2 microglia release anti-inflammatory mediators and induce anti-inflammatory and neuroprotectivity. Microglia-mediated neuroinflammation is considered as a double-edged sword, performing both harmful and helpful effects in neurodegenerative diseases.

And again, there are nuances and corrections: some authors see further differentiation of phenotypes, and others see different types of microglia. Fact is, either microglia can do bad instead of good, or microglia can move from a state where they do more bad than good and perhaps even vice versa.


Neuroinflammation as the polarizing trigger

The amount of neuroinflammation seems to be the trigger here. Viruses and misfolded proteins can trigger this neuroinflammation, but it appears that age as such is the main risk factor for chronic altered inflammation. “Aging is considered the main risk factor for several neurodegenerative diseases and is accompanied by chronic altered inflammation involving changes in microglial morphology, phenotype and activity.

In short, where maintenance and repair are associated with the beneficial microglial phenotype, inflammation, cytokines and neuronal death are associated with the detrimental phenotype. The latter phenotype is associated with neurodegenerative diseases, or even mood disorders, psychiatric disorders and depression.

Or still, chronic neuroinflammation and microglia-driven neurodegeneration correlate and are part of the same deal.

So, when INmune Bio announced its nine presentations at the AD/PD conference, that’s how one should understand the following sentence: “Conference Provides First Exposure of EU and UK AD Experts to INmune Bio’s Approach of Targeting Neuroinflammation and Glial Activation with XPro™ for Treatment of Alzheimer’s Disease.”

Furthermore, one of their posters was entitled: “White Matter (WM) Abnormalities Correlate with CSFBiomarkers of Microglial Activation and Pathological Tau in Alzheimer’s Disease”?

The (tiny) glial cell has always been around in the following slide on INmune Bio’s corporate presentation (and those percentages are speaking):




The following slide (partial copy) is new:



How much bad can our brain caretakers do?

A lot of bad. Look at it like a gardener that doesn’t come by to take care of the garden any more.

To say it with the words of Beth Stevens, in the framework of AD:

So, the question is, you know, putting all this together, could microglia be actually mediating some of this synapse loss through some of these mechanisms, including the complement cascade? Now, it's well known that microglia dramatically alter both their morphology and function in the context of diseases like AD. They go from this really beautifully ramified microglia that I told you about in the first part of my talk, and they become quite different, and, quote unquote, "activated". They increase a lot of phagocytic receptors. They become more lysosomal, there's more lysosomal activity. But the problem with this sort of shift in morphology is, it really doesn't tell us when these cells changed or, at least by morphology and with this handful of markers, whether they're actually contributing to the detrimental or specific functions in Alzheimer's disease. Now, it's been thought for the most part, until recently, that microglia dysfunction was sort of a secondary event. But emerging genetic studies, especially in late-onset Alzheimer's disease, more and more are implicating microglia and myeloid cells as being key drivers in Alzheimer's disease, at least late-onset Alzheimer's disease.




In fact, almost half of the late-onset AD risk genes, which are over here, a lot of these are common variants [that] are actually expressed in or enriched in myeloid cells. And even APOE, which we know is a critical risk factor in Alzheimer's disease is indeed upregulated and expressed in microglia, both in human AD brains as well as mouse models. So, putting all of this together, this is a sort of chance to change the way we've been thinking about microglia in the context of Alzheimer's disease. And so, the big question that we've also been focused on is, do microglia contribute to synaptic and cognitive impairment in Alzheimer's?

Source


The very clear relationship between microglia and Alzheimer’s disease

The picture above already showed that immune and microglia gene expression are highly correlated to Alzheimer’s disease, and these include ApOE4 and TREM2.

Alector made this more specific: 75% of AD risk-genes are microglia-specific. That’s 22 out of 29 genes.



Source: alector company presentation.


Prof. Ed Bullmore, a neuroscientist who is professor of psychiatry at the University of Cambridge, mentions in his meanwhile world-famous bestseller ‘The Inflamed Brain: a Radical New Approach to Depression’s chapter ‘Alzheimer’s disease and the yin and yang of microglia’: “In fact, it seems that the secondary, inflammatory reaction of the microglia could be a more potent cause of death of nerve cells, and therefore a more powerful driver of progressive loss of memory and other cognitive functions, than the primary problem of plaques and tangles. […] Conversely, untreated infection or inflammation in the body is recognized to increase the risk of Alzheimer’s disease and to accelerate the rate of progression of dementia. The inflammatory cytokines pumped into the circulation by macrophages dealing with a chronic infection like periodontitis, say, can get across the blood-brain barrier (BBB), and activate microglia, making them more likely to respond aggressively to amyloid plaques and increasing the collateral damage to nerve cells.

Alzheimer’s isn’t one thing and the brain’s innate immune system is at least two things, yin and yang, protective and self-destructive. This is not classic blockbuster territory. It’s never going to be one size fits all, therapeutically, but you sense there could be some good opportunities to develop personalized immune treatments for Alzheimer’s disease in the next 5-10 years.” The book concludes: “Maybe we’ll see new drugs that, unlike the old drugs, are not vaguely supposed to work equally well for everyone with depression but are scientifically predicted to work particularly well for some people.


Prof. Bullmore is currently leading a consortium funded by among others GSK, Janssen and Lundbeck which is exploring immune mechanisms and therapeutics for depression and dementia.


INmune Bio will soon start its Phase 2 trial in treatment-resistant depression, next to its trials in Alzheimer’s and Mild Cognitive Impairment, and has abundantly stated XPro could target any neurodegenerative disease. Alector is targeting microglia and is reporting a 54% slowing of decline in frontotemporal dementia. Brainstorm Cell Therapeutics is targeting microglia and astrocytes for ALS.


That goes to show: microglia-driven neuroinflammation and neurodegeneration are key to treating more than just one neurodegenerative disease, perhaps even most or all of them.. The patients-specific approach, or enrichment strategy as INmune Bio calls it, is a view that I have seen returned so many times in all the scientific articles I have read. Surely soon, when INMB will start its trial in TRD which will only target patients with an ‘inflamed brain’, so to speak, TRDi may pop up.


Bottom line: balance of (micro)glial activity is essentially a main target of drug development. Astrocytes also play a role in synaptic development, but it appears the role of microglia is greater.


Alzheimer’s disease may need to be approached as a white matter disease

I mentioned earlier that the amount of glial cells differs from one brain region to another, and that in the white matter, the proportion of glial cells to neurons is substantially higher.

Some months ago, INmune Bio’s CEO, RJ Tesi, wrote an article that was entitled: ‘Alzheimer’s disease should be approached as a white matter disease, not gray’. That article approached things from a different perspective, namely direct neuroimaging evidence of this thesis. It also mentioned:

However, white matter changes have been shown to develop very early, in prodromal phase (pre-Alzheimer’s) and precede the onset of clinical symptoms of dementia, underscoring the importance of their further investigation and focus.

My sense of logic says this: if microglia are the main culprits of neurodegeneration, then the areas where they are most may suffer damage first and most intensely.


Glial ignorance by big pharma and most of biotech

Despite the abundant focus on microglia in the current state of the science, biotech and big pharma companies in the neurodegenerative field show a remarkable absence of focus on that same immune cell. The word inflammation occasionally does pop up, but often still as an aside, whereas it should be on the forefront.

This is not the case for Alector, Brainstorm Cell Therapeutics, Denali Therapeutics and INmune Bio. In part due to their impressive partnerships, both Alector and Denali Therapeutics have impressive market caps, even if both have well come off their year highs. Alector had a $2.2 billion deal with GSK with a $ 700 m. upfront payment in 2021, and with Biogen, Denali signed a $ 1 billion partnership deal with a $ 560 m upfront payment. Much of their interesting pipelines, certainly in the case of Denali, are still very early stage.

So, what does Brainstorm Cell Therapeutics say about astrocytes and microglia in this explanatory video: “Astrocytes, an important cell type in the brain, bring nutrients and survival factors to nerve cells. Microglia, other important brain cells, drive inflammatory responses against pathogens in the brain and spinal cord. In ALS, astrocytes lose their nerve support and microglia promote chronic inflammation. Both of these contribute to loss of function and nerve cell death. Nerve cell death could also be caused by immune cell activation in the central nervous system, CNS. This includes resident microglia and invading immune cells acting together and releasing molecules that trigger a storm of inflammatory responses that worsen disease progression. [explanation about Nurown]


And INmune Bio, in this video:

When white matter is healthy, one's ability to think, speak or move is rapid and efficient, but when it degenerates, many of the brain's functions become impaired, which is an early pathological event in many neurodegenerative diseases.

This process of neurodegeneration is executed by immune cells. The first sign of brain disease occurs as immune cells interrupt neuronal communication, break down synaptic connections, and strip axons of myelin. As the disease progresses, axons degenerate and finally neurons die. While neuron death is irreversible, white matter can potentially be repaired. Repairing white matter may restore the ability of neurons to communicate and improve cognitive function. [Explanation about XPro and Imeca]”


Conclusion

The conclusion here is: neuroinflammation and targeting glial cells are part of the same deal.

In ‘rebalancing’ the microglia, one should be able to drastically impact treatment of Alzheimer’s disease, and possibly of any neurodegenerative disease, including mood and depression disorders. If that rebalancing leads the microglia to start repairing again, stop their destructive actions and stop firing off inflammatory cytokines, then the brain could return to a more healthy state.

AD drug development seems to not have caught up with this new paradigm yet. It’s however a major topic in the most recent science. Early results from different companies seem to show that this is thé pathway to target.



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