PART Two

PROVIDENCE – The breakthrough research conducted by the team of scientists at MindImmune to develop a new drug candidate to halt Alzheimer’s disease, “nipping it in the blood” before it reaches the brain, represents a fundamental challenge to the scientific dogma about how the brain’s immune system functions, according to Stevin Zorn, the founder and CEO at MindImmune.

MindImmune, a drug development enterprise imbedded at the University of Rhode Island, plans to enter the clinic in 2026 to test a new drug candidate, MITI-101, to seek to counteract Alzheimer’s disease – before it reaches the brain.

MindImmune’s novel approach heralds a remarkable shift in biology and strategy on how best to treat other chronic autoimmune diseases – treatments that are focused on what is known as the process of immune cell recruitment (immune cells that originate in the blood, not the brain).

“We believe that we can stop this disease by stopping these cells in the blood,” Zorn explained, during an in-depth interview conducted by ConvergenceRI on Thursday, Sept. 25. [See link below to ConvergenceRI story, “A scientific breakthrough on treating Alzheimer’ disease.”]

“Our strategy is a novel approach,” Zorn continued. “It is kind of bucking dogma.”

What do you mean when you say: “Bucking dogma?” ConvergenceRI asked. 

Zorn answered: Dogma means, in this case, the dogma that immune cells don’t get into the brain. They are already there. “We have spent a lot of time and work demonstrating that this dogma is fiction – that immune cells actually do get into the brain.”

Understanding the process of immune cell recruitment.    
Zorn detailed the discoveries that led to a changed understanding of the biology of Alzheimer’s disease. “There is a whole literature now of immune cell recruitment that has been published, demonstrating that immune cells have the mechanism to get into the brain,” he said.

Zorn continued: “So, this whole notion that the brain is 'immuno-privileged' – that it is a big box, with a big blood brain barrier that nothing can get through -- is just not the case.”

Zorn then described the strategic changes in the biology. “Immune cells can go in and out of the brain. They know how. They can communicate with the immune cells in the brain. They can leave the brain and communicate with other immune cells. And, they can go back and forth and work together to either cause or prevent disease.”

The problems with building antibody treatments for the brain    
Zorn then detailed the problems with the previous approach. “What’s remarkable about that is that there are a lot of people – a lot of companies – that are working to build antibody treatments for brain diseases. The trouble with those treatments is that they don’t get into the brain very well.”

Antibodies, Zorn continued, “don’t penetrate the blood brain barrier very well. So, there are all these sophisticated techniques that companies are using to try to get their molecules into the brain. But standard antibodies only get into the brain about a half a percent [0.5] to maybe 1 percent of what is in the plasma. And so, when you administer those drugs, you have to administer a lot of them, in order to get enough of the exposure up, so that half of a percent, or 1 percent, actually gives you sufficient brain amounts to be therapeutic. The trouble with that is that you are giving such heroic amounts of drugs so that you can have off-target side effects, either in the brain or, in particular, in the periphery. You have to give so much of these antibodies you have to figure out: what are they going to do that they are not supposed to do.”

A 30-year scientific journey    
MindImmune’s breakthrough in strategy reflected a 30-year research exploration. “The fact that we [at MindImmune] are treating a target in the blood means that we don’t have to cross the blood brain barrier,” Zorn said. “That means that the concentrations of our antibody that are going to be effective to inhibit these cells from recruiting are going to be the concentrations that the blood cells see when we administer [the antibody] in the blood. And, that will probably be a hundred times or more lower concentrations [emphasis added] than traditional antibodies.”

The implications are that the change in strategy will improve safety, Zorn continued. “That could bode for better safety than the traditional antibodies that have to get into the brain, and less off-target effects because we are going to give less drug. It will probably lower the cost of goods because we don’t have to deliver boatloads of drug in order to get small amounts into the brain. That should reduce cost of the medication, ultimately, and simplify the manufacturing process.”

Zorn spoke of the excitement in entering the clinic to test a new drug candidate, MITI-101. “I think this could herald in a whole new era of different types of treatments,” Zorn said, exploring how things in the periphery can affect the brain. “We see that these immune cells in the periphery have a way of getting into the brain. In the olden days, and the olden days are only 20 years ago, the brain was considered immuno-privileged. Immune cells don’t get into the brain. They must already be there. We published a paper last year reviewing the literature about this, and there is actually quite a bit of literature with these so-called fate-mapping studies, which map these immune cells that we are looking at and discovered that these immune cells have an origin in the bone marrow. Bone marrow is in the periphery; it’s not in the brain.”

What Zorn and his team discovered, he continued, “was that microglia, which are the brain resident immune cells, the innate immune cells of the brain, their origin is not in the bone marrow. So, when we develop as fetuses and into babies, different cells are the kind of the progenitors of where the cell ultimately ends up. And what is the primitive yolk sac, kind of like a chicken yolk, but the yolk sac of a human being, is where microglia are born from. And so, you are basically born with microglia, those microglia, those innate immune cells of the brain, are already in the brain when we are born and as we grow up.”

As a result, Zorn explained, because “these cells that derive from the bone marrow, they get into the brain and we believe that they have been misidentified as microglia in some cases. Some investigators have actually named them different subtypes of microglia. But they bear all the markers of the cells that we are seeing in the periphery.

[Our strategy] is a novel approach. It is kind of bucking dogma.

ConvergenceRI: What do you mean when you say, “bucking dogma?”    
ZORN: Dogma means, in this case, the dogma was that immune cells don’t get into the brain. They are already there.

What we have been doing, since the last time we spoke, we have spent a lot of time and work demonstrating that this dogma is fiction: that immune cells actually do get into the brain.

And, while we were doing that, we weren’t the only ones. There is a whole literature now of immune cell recruitment that has been published, demonstrating that immune cells have the mechanism to get into the brain.

So, this whole notion that the brain is “immuno-privileged” – that it is a big box, with a big blood brain barrier that nothing can get through, is just not the case.

Immune cells can go in and out of the brain. They know how. They can communicate with the immune cells in the brain. They can leave the brain and communicate with other immune cells. And, they can go back and forth and work together to either cause or prevent disease.

ConvergenceRI: That’s a really important point. I want to make sure that I am stating it correctly, accurately, in your own words, with what you are comfortable saying. [Pause] This is really thrilling. I feel privileged to be able to report on this story. I sense that you have been very cautious – not wanting to get too far ahead, leaning out over your skis.    
ZORN: Yes, that’s right. When the whole world is focused on one place, and if our data is pointing to something else, before we go out and start to talk about that, we’ve got to be pretty sure of it.

Proving first to ourselves that immune cell recruitment into the brain is real, and then two, once we convinced ourselves, we started going out and finding evidence to support the notion that that really happens. We found that support with other investigators that have published this work, with our own work, and now we are taking our work to task.

ConvergenceRI: I want to say congratulations, great work.    
ZORN: The Ryan Institute at URI, they were very critical in this process. They believed in us when we first came to them, looking to build our company. To collaborate with us. To give us a place to set up our company. I think that URI has really been very supportive of us. I think that is great.

We want to continue to keep our relationship with URI strong, with the Ryan Institute strong. It takes a community to cure and to treat a disease. And the Ryan Institute is focused on Alzheimer’s disease, in part. It’s going to take not only them, not only all of the biotech centers, around the East Coast and the West Coast, it’s going to take a lot of experts around the world to kind of nip this in the blood. That’s our hypothesis. We started it here. And we’ll continue from there.

ConvergenceRI: What questions haven’t I have asked, should I have asked, that you would like to talk about? What are the most important questions moving forward that people need to get answers to?    
 ZORN: What is the safety of your product? That’s something that we will determine as part of our IND enabling work. We will do toxicology studies to try and demonstrate safety. We feel pretty good about that. In the sense that antibodies are generally pretty safe molecules. So many of them have been through toxicology studies, with a structure not too much dissimilar from what our antibody structure is. They have soared right through toxicology studies and made it into the clinic without issues.

We think our antibody will be structurally safe. We know from knockout studies that if you take our target and you genetically engineer mice so that they don’t have it, they are viable, they are fertile, they can reproduce, they don’t die, which means that if you knock out this target, it’s not a lethal event. It’s not a dangerous event.

ConvergenceRI: Will you be working with mice, before you work with humans? Will you be working with, say, fruit flies, or will you be going directly to humans?    
ZORN: All of the experimental work that we have done to date has been with laboratory animals. This is an interesting distinction here, Richard. The work that we did we did not discover in mice. The work that we did is a direct translation of everything that we’ve seen in humans.

Human post-mortem Alzheimer’s brain has pointed the way. Gene-wide association screens have pointed the way in human material. Genetic testing has pointed the way. All of which identified what we are working on. And then, in humans.

And so, we then went to mice and started looking: Do we see the same thing in the mouse? Can we find the CD 11 C cells in a mouse, a model of Alzheimer’s pathology? And, sure enough, we did. We saw that.

And then, more recently, we have been collaborating with some groups up at Harvard who have been publishing studies in patients --  people who have heads full of amyloid plaques, and other patients who have dementia, and others, they are not patients, they are people with heads full of amyloid plaques that don’t have dementia.

They don’t have any cognitive decline at all. As many as 30 percent of people with those hallmark pathologies of Alzheimer’s disease don’t have dementia; they don’t have the cognitive deficits.

And, what seem to be the differentiator between those that get the disease, and those that don’t, and this was published by those Harvard researchers that we are collaborating with, and a group before them, is the presence of these immune cells in the Alzheimer’s brains and synaptic damage that is caused by these immune cells.

You don’t see that in those cognitive resilient people. And what we found is that we can convert our Alzheimer’s pathology mice with our antibody into mice that don’t have those cells in their brain. We can keep them out, and as a result, of that, we don’t see that synaptic damage, after multiple days of treatment with the antibody. It almost, it is not exactly, but it almost recapitulates what the clinical findings are.

And that is what we’ve done all along. We took a clinical finding, and we tried to find something in an animal that modeled that. And when we found it, we then expanded on that.

We found something in a mouse; we didn’t want to believe that until we saw something similar in a human tissue. Or somebody published a biomarker in a human immune cell that was very much like ours. And so, a lot of those pieces are coming together.

So, it is not a hypothesis that was born in a mouse. It was a hypothesis born in humans, translated into a mouse, and then translated back to humans. 

And now, what we want to do is to take it back to the human and test it and see if it works.