KINGSTON – The four principals of MindImmune Therapeutics, Inc., a promising for profit drug discovery venture embedded at the George and Anne Ryan Institute for Neuroscience at the University of Rhode Island, could have become yet another early stage firm drawn to locate its emerging enterprise within the sphere of the innovation ecosystem of Boston and Cambridge in Massachusetts.

Instead, Stevin H. Zorn, the president and CEO of MindImmune, Frank S. Menniti, the chief science officer, Robert B. Nelson, vice president of Exploratory Biology, and Brian Campbell, vice president of Pharmacology, chose to develop an innovative research hub at URI, focused on efforts to target the pathologic process of neuroinflammation to treat neurodegenerative disorders, such as Alzheimer’s disease.

Together, the four scientists combined bring more than 100 years’ worth of world-class Big Pharma experience in drug discovery to the quest: to develop a platform of new therapeutics to respond to the converging evidence, including new genetic findings, that indicate the malfunctioning of the immune system is a key cause in brain disease and central nervous system disorders.

“Reducing neuroinflammation heralds significant breakthroughs in the treatment of brain disease, much as targeting immune activity is revolutionizing the treatment of cancers,” Zorn said, calling it “the link we have missed” in many previous efforts to develop therapeutic approaches to neurodegenerative diseases.

All previously worked at Pfizer, Inc.; Zorn, Nelson and Campbell were formerly employed at the Paramus, N.J.-based operations of H. Lundbeck A/S, a Copenhagen-based global pharmaceutical company specializing in psychiatric and neurological disorders, where the three led the development of a first-in-industry neuroinflammation group.

Menniti previously served as co-founder and chief scientific officer of of the Providence-based Mnemosyne Pharmaceuticals, now Luc Therapeutics Inc., a drug discovery venture focused on neuropsychiatric disorders, which in 2015 signed a pre-clinical drug deal potentially worth nine figures with Novartis.

In 2016, MindImmune, in partnership with URI, created a unique research platform, enabling the for-profit firm to locate itself on the URI campus, building a collaborative research hub with the university’s growing scholarship in biology, pharmacology and neuroscience. [See link below to ConvergenceRI story, “To go where no research enterprise has gone before in Rhode-Island.”]

The MOU between MindImmune and URI is the first of its kind in Rhode Island, according to both Zorn and Paula Grammas, Ph.D., the inaugural director of the George & Anne Ryan Institute for Neuroscience.

In turn, each of the four founding members of MindImmune’s scientific team has been appointed as research faculty at the Ryan Institute.

The key ingredient in this convergence was an initial seed investment by the Slater Technology Fund of $500,000 in 2016.

On Monday, Aug. 21, Slater is scheduled to announce a new $250,000 investment. Coupled with an additional $250,000 investment from private sources, MindImmune is positioned to begin raising money for a Series A equity round of financing.

“MindImmune brings together a team of world-class drug discovery scientists pioneering a fundamentally new approach to the treatment of neurodegenerative disease,” said Richard G. Horan, senior managing director of the Slater Technology Fund, in the news release announcing the new investment.

More than just the additional investment in MindImmune, the story is very much about the strategic role that Slater Technology Fund played in bringing this enterprise to fruition and keeping it in Rhode Island.

As Menniti told ConvergenceRI, “Slater invested $750,000, and it allowed us to stay in Rhode Island.”

Zorn agreed; the Slater investment “enabled us to incorporate and become a company in Rhode Island, which is where we want to be.” It allowed us, Zorn continued, to build a relationship with the University of Rhode Island.

Zorn expressed gratitude for Slater’s continued support. “We are grateful to Slater for believing in us, for doing the due diligence on our science, and investing in us,” Zorn said. “Rich [Horan] is working hard to help bring other Rhode Island investment into MindImmune. Our limitation, as always, is the availability of funds; it’s not a limitation on ideas.”

Here is the ConvergenceRI interview with the four principals of MindImmune, Inc., as they describe their innovative enterprise focused on drug discovery looking at neuroinflammation as the cause of brain disease and, at the same time, creating a research hub in neuroscience at the University of Rhode Island.

ConvergenceRI: MindImmune is on the cusp of some very interesting dynamics and developments. With the latest Slater investment, you’ve raised $750,000 in seed investment? Can you describe the current landscape?
ZORN: There is also a private match of $250,000, to bring the seed investment up to $1 million. We are just about to start raising money for our Series A equity investment.

We are building a portfolio and we’re negotiating licenses to intellectual property. We are very close to closing on those negotiations.

ConvergenceRI: What do you mean by closing?
ZORN: We have pretty much finished our negotiations. And now we’re at the contract [stage]. The names of the companies that we are negotiating with are still confidential.

ConvergenceRI: Will that help kick off the Series A fundraising?
ZORN: No, the Series A fundraising is being kicked off now, where we are clear to start work as soon as we have sufficient funds.

Everyone that contributes to Series A will be buying into the whole company, and the whole portfolio, and so will support the whole portfolio.

But funds will primarily suppot this project through reseaerch done by us at URI.

We’re ooking at public funding – SBIRs and government funds – to supplement our work in a non-diluting way to move our other projects forward.

CAMBPELL: We have also recently submitted an application to enter one of our programs into the Blueprint for Neurotherapeutics network, a NIH program that provides hands-on resources for drug development for brain disease. The Blueprint network set up by NIH has pre-negotiated contracts with various vendors to provide essential drug discovery capabilities.

There are multiple stages at which nascent companies can use these Blueprint resources.

Our company is aplying to Blueprint to take the lead compounds from one of our programs through an Investigational New Drug application and into Phase I clinical development.

What’s really nice about that program is we lead, and they fund the work through their outsourced networks, using validated NIH contract research organizations  and, as Stevin mentioned, it can be millions  of dollars worth of non-diluted funding.

ConvegenceRI: But you retain the intellectual property?
ZORN: That’s correct. We are negotiating the intellectual property rights for the lead compounds . Once we have the IP signed over to us, the compunds are ours. And, then on the basis of having the rights to these molecules, we will  advance them either through direct funding or through SBIR/Blueprint government funding.

If it’s government funding, the rights stay with us. If it’s private funding, there is equity that is proffered for that funding.

ConvergenceRI: Could you step back a bit and describe the science that you are pursuing with MindImmune? As I understand it, you are looking at the way that the brain deals with inflammation as a key to how to treat a variety of central nervous system diseases.
ZORN: We are pursuing various approaches to treat neuroinflammation. There is an immune system in the brain, and there is an immune system outside of the brain. And, there’s communication between what happens outside and what happens inside the brain. And, we’re trying to work with those systems to affect brain diseases.

MENNITI: When we talk about the immune system, most people think of it as what happens when you have an inflammatory disease – what happens when you have a cold.

Your immune system acts up and it attacks either the virus or the bacteria that is making you sick.

The immune system actually does much more than that. It’s the body’s maintenance system. It’s involved with helping cells build an environment in which they can exist, it takes out the trash, it maintains the plumbing.

And, when there is damage, or when there is an infection, the immune system ramps up and takes on a different role, to deal with the damage, to stop the damage. When it’s done that, it then goes into a reparative role.

So, you could imagine, if you’ve got a house, you maintain the plumbing, etc. If there’s a fire, the fire department comes in, puts out the fire, and then you have to rebuild whatever was burnt down.

The immune system performs all of those functions in different ways.

But, sometimes, when the immune system gets activated, it gets out of whack.

Imagine if you have a fire in your house, and the fire department comes and starts [spraying] water to put out the fire – but they never stop. Pretty soon, the damage by the fire department is much, much worse than the damage from that original fire.

And, that’s essentially the basis of chronic immune diseases, such as atherosclerosis or psoriasis.

Here’s the thing. We never really thought that the immune system played those functions in the brain. Now, we know that the immune system in the brain does exactly what it does in the rest of the body.

[Zorn shares an image of a slide on his phone, showing inflammatory cells that are stained in association with diseased tissue for a number of brain disorders – including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and depression.]

ZORN: Everywhere we looked, be it psychiatric or neurological diseases, neuroinflammation has been found to be a player.

MENNITI: Some of this data is 20, 30 years old. But the issue is: no one has ever been able to really figure out what the meaning of that is. Is it good? Is it bad? What has changed our understanding is recent human genetics datra in each of these diseases.

The genes that pop up – that contribute to disease risk, tend to be related to the immune system.

Before, we knew that the immune system was active; we didn’t know whether it was good or bad. But now, the genetics tell us, yes, this is actually bad.

And, that realization actually opens a whole new avenue of thinking about brain disease.

Bob [Nelson] has been working on this for 20, 25 years. When we worked together at Pfizer, we all thought he was nuts. [Laughter.]

ZORN: But he wasn't nuts. By focusing on the immune system, it opens a new vista into how to think about brain disease and the cutting-edge ways to treat it.

That is where our experience in drug discovery comes in. We have actually been able to identify what we think are several programs that are in various stages of development that are probably the best opportunities right now to start to target the immune system to treat brain disease.

MENNITI: When these guys left Pfizer, they went to Lundbeck, where they really started to dig into this, and they formed the first group in industry solely focusing on targeting the immune system in central nervous system diseases.

When Lundbeck decided to shut down the site at Paramus, we all got together to pursue drug discovery in neuroinflammation, just as the Ryan Institute was getting started.

Paula Grammas has been focused on a different perspective – the vascular system in the brain, the blood vessels, something that therapeutically has been ignored for years.

Now, with MindImmune and the Ryan Institute [collaborating], there is this realization that the combination of the immune system and the vascular system are integral parts of the brain and they contribute to brain diseases.

ZORN: What Frank [Menniti] said before about the house on fire, although the analogy is a very simple example, it does describe the problem.

The major focus for Alzheimer’s disease research, such as beta amyloid and tau [as the trigger and bullet], have been chased for decades, with no therapeutics to show for their efforts. Some [researchers] are beginning to recognize that going after beta amyloid or tau directly may not be the best way to go, because maybe what those things are doing is activating the immune system.

With the toxicity of beta amyloid and tau, you have the fireman spraying water, and if it isn't turned off, it will keep doing damage. Basically you’re going to kill the brain from neuroinflammation.

The fireman spraying water with the hose, if it isn’t turned off, it will keep doing damage.

NELSON: There is a less metaphorical nuance to this work that I believe is important, regarding what the immune system is doing in the brain.

In addition to the function of immune cells being designed to gobble up bacteria and viruses in order to protect us, a research lab at Harvard has discovered that during brain development, the immune cells in the brain gobble up the [extra] connections between the neurons.

This process, which is essential to brain development, apparently gets turned back on in diseases such as Alzheimer’s disease, where it becoms a disaster: the immune cells are trying to help but it is leading to a disruption of the essential connections between the neurons that the adult brain needs to function.

Part of what we’re trying to do is to figure out which of those immune cells are causing this to happen, and how to turn that process off, in order to preserve your ability to think.

ConvergenceRI: Is it difficult to talk about your work? Does it require a new kind of language, to build a bridge between immunology and neuroscience?
ZORN: That is a good question. As complicated as neuroscience is, you have the immune system, which is just as if not even more complicated. Immunologists have been studying the immune system for many decades, building a language and talking among themselves. And, neuroscientists have been doing exactly the same thing, talking among themselves.

And, sure enough, as these two fields have come together, there is a recognition that neuroscientists don’t speak immunology, and immunologists don’t speak neuroscience.

It was like two ships passing the night.

But, once we started to talk about the problems we have identified with those neurons, and they started talking about what happened with immunology,  we began to realize that we were dealing with the same molecules.

The lessons from cancer biology, which have been fruitful lately, is that you can develop treatments for diseases that are related specifically to what you can define as a molecule in immunology.

It is the same in the brain; but people didn’t actually think that these things were doing the same thing to the brain. So, that’s the missing link.

ConvergenceRI: With neuroscience, does it come laden with projected expectations, such as the next space age in research and the source of a new wave of job creation?

MENNITI: I think the idea that you mentioned, that neuroscience is an area that is exploding and can become an engine for economic gtrowth, is absolutely true.

The reason why there is an opportunity is because, it the last 10 or 15 years, our understanding of the way that the brain works has increased exponentially.

NELSON: What we have known about Alzheimer’s disease is amyloid plaques and neurofibrillary tangles since 1907, when Alzheimer first described them.

Since then, the science has been focused upon: can you take them apart and find out what they’re made of. That’s the biology.

Along the way, we found that immune cells are associated with both of these structures; the genetics keep telling us that these immune cells are involved in the disease directly.

This is very new; it’s subtle. There are a whole lot of genes that are contributing a little bit. It’s incontrovertible that they do have a role in the disease. Now, we’re trying to understand more about who those cells are, and what they are doing, how they mess with the brain’s wiring.

ConvergenceRI: How has the research partnership with URI and the George and Anne Ryan Institute for Neuroscience served as a catalyst for work? What makes the relationship special?
MENNITI: There are two aspects to drug discovery. One aspect of drug discovery is coming up with a molecule that goes in the bottle. Then there’s a skill set that’s involved in identifying what to put in that bottle, and why.

ZORN: There is a set of characteristics about molecules that are developed that have to be achieved for them to become “druggable.”

These are physical and chemical properties that these compounds have to have in order to get into the brain, and to get into the cell and get to the target.

There are other principles about understanding how your hypothesis works, and being able to do enough work to be able to demonstrate that your hypothesis is at play in the human condition when you’re testing a drug – whether you are cloning drugs, compounds or genes, or just coming up with basic research ideas.

This is a long process that is very complicated, to convert an idea into a drug discovery idea, and then convert that drug discovery idea into a drug, and then do clinical testing.

ConvergenceRI: And, it’s a very expensive process, too.
ZORN: Yes, it’s a very expensive process, and it requires different skill sets. At Big Pharma, for example, companies have a wonderful skill set in developing those drugs and bringing them forward.

On the other hand, academia has a wonderful skill set of doing basic research and coming up with interesting targets and ideas. That is the purview of basic research that is typically associated with academia. To understand what to put in the bottle, and why to put it in there, and what to do with it once you’ve gotten it in the bottle, you need to do a lot of basic research.

At big companies, the resources went into putting things in bottles, and that was something that they did incredibly well. The research tended to come from the outside, in bits and pieces, and it was kind of hard to control, because the stuff that was coming in often wasn’t actually answering the questions that we needed answers to.

Many of the basic researchers here [at URI], they have all these ideas, but they don’t have the pharmaceutical background to make medicines. 

So, coming into the Ryan Institute, for us, is nirvana. We’ve got all of this basic research going on in a hihg-quality research environment, and it’s not only at the Ryan, it’s at Brown, it’s at any other research institution in the state that we can work with, or any other place in the world, for that matter.

The real magic here with MindImmune at URI is that we have 100 years of expertise in actually taking these discoveries and converting them into drugs and bringing them to patients, and in some cases, some of those drugs actually made it to the marketplace and are helping millions of patients around the world.

To work together with them on how to take these ideas, and transform them into drug discovery ideas. That requires a certain finesse and know how and collaboration.

And, that’s what the Ryan Institute at URI saw in us; we have that finesse and know how. They embraced us as the first four research professors at the Ryan Institute, to be able to collaborate with the research environment at URI to help build companies or help convert ideas into actionable drug discovery ideas