Mukesh K. Jain, M.D., remembers the exact moment that COVID-19 complications clicked into focus for him. Like most of us, the cardiologist was devouring news reports and scientific articles about the novel coronavirus the moment they came out.

In early April, a few months into the global pandemic, news started to trickle out about some of the disease’s more bizarre and serious effects: strokes, heart attacks, and purple toes. Jain and his colleagues saw an immediate common thread among these unusual complications.

“It was so obvious that the vasculature was likely a major contributor in all these manifestations,” Jain said. “The complications point to abnormalities in function of blood elements or blood vessels.”

It so happens Jain and his colleagues were working on a new class of treatments for just that problem, but with a very different application: Alzheimer’s disease and other forms of dementia.

We caught up with Jain, a physician and researcher at University Hospitals and Case Western Reserve University, to find out more about the new class of dementia treatments he and his team members are developing through the American Heart Association-Allen Initiative in Brain Health and Cognitive Impairment award – and why he thinks these treatments could also help those most at risk from the novel coronavirus. Jain and his colleagues are hoping to get some of these new treatments into clinical trials for COVID-19 patients by this coming winter.

The following interview has been lightly edited for length and clarity. For more, listen to the second episode of our Lab Notes podcast.

How could a problem with blood clotting cause these serious symptoms in COVID-19 patients?

When blood vessels get blocked, it can cause a whole suite of different problems in the body. You get a decrease in oxygen and nutrient delivery, and that results in tissue injury where the blockage occurs. That lack of oxygen is most evident in COVID-19 patients with lung injury. These lung injuries are really complicated, but amongst the reasons you have lung damage is because when blood vessels in the lungs become dysfunctional, they start to leak, and then clots form and the air sacs of the lung get plugged up. Your ability to take oxygen up in the lung and pass it off into the blood vessels to supply the body is then reduced, and that causes even more problems.

You’ve been studying the blood and vasculature for a few decades now. Why is this system so important?

You can think of blood vessels like the body’s highway system. The large vessels are like a large highway that then breaks up into smaller highways, then smaller roads, until you get to what’s like the driveway to each house. That’s the small blood vessel that supplies each cell. And that system has two major functions: to deliver energy in the form of oxygen and nutrients, and to deliver defense in the form of immune cells that can help protect your tissues. The blood vessels are absolutely requisite for supplying these two essential systems, metabolism and immunity, to all our tissues.

You’ve recently started researching how the vasculature affects Alzheimer’s disease and other forms of dementia. How did you make those connections?

It’s actually a very simple idea. Your brain is only about 2% of your body weight, but it consumes 20% of all your energy. The brain does not have its own energy stores; it is entirely dependent on energy from blood vessels. You know that’s important, because if you lose blood supply to the brain for just a minute, you’ll pass out, and just a few minutes later, you’d suffer permanent brain damage. That just underscores how vitally important the blood supply is to proper brain function.

We also have some intriguing evidence that there’s a connection with dementia. We know that the risk factors for heart disease and dementia overlap significantly, and other studies have found that in the brains of people who have passed away from dementia, there are these little lesions all over from where small blood vessels have collapsed. You can imagine when a small blood vessel collapses, a handful of brain cells will succumb. If that happens once or twice and you lose a few brain cells, maybe it’s not a big deal, but if it happens to hundreds or thousands of blood vessels, now you start to have a cumulative effect. That has been seen in patients with dementia.

What can be done about this blood-related damage?

There are a couple different approaches we’re taking, and they basically boil down to two concepts: Keep the highways and roads open; and make sure that the cargo, the nutrients and oxygen, get delivered. One compound we’ve been working on, ethyl nitrite or ENO for short, mimics a natural process in the body that allows hemoglobin to deliver oxygen more efficiently. We’ve also been studying a protein known as KLF that helps maintain the inner lining of blood vessels, the endothelium, which keeps blood flowing smoothly so it can deliver its content to the tissues. The endothelium is crucial so you don’t get blood leaks and clots and the roadway is clear for blood flow. There are existing drugs that enhance KLF and we’re testing some of those in the lab right now. We’re working on another therapeutic, P7C3, which actually acts on both aspects. It helps keep blood flowing smoothly, and it helps with energy production in the body’s cells.

So how does this all tie into COVID-19?

The way I think about it, there are two components to COVID-19. There’s the viral component, where you need antiviral treatments and vaccines, and thankfully there are a lot of people working on those. And then there are the complications of the disease: injury to the lungs, the brain, the heart. That’s where I think our work can come in. The work that we’re doing right now with a focus on dementia – therapies that could keep the blood vessels open and therapies that optimize the delivery of oxygen – would all be very logical approaches to treating the oxygen deficits that you see in COVID-19. The patients who are gravely ill typically have the greatest risk of blood clots and oxygen deprivation, and so I would predict that these therapies would be of most help to patients with the most severe illness.

How far along are these therapies – when could they be used in patients?

My hope is we could get approval for ENO in the next couple of months, so we would be able to administer to patients in the ICU initially, sometime before the end of the year. And this other drug I mentioned, bortezomib, that enhances KLF function and keeps the linings of blood vessels functioning, is already approved for other uses, so I’m hoping we will get approval to test that therapy in COVID patients within the next few months as well. P7C3 is really very exciting but will probably require a bit more time before entering patient studies.

In the best-case scenario, what do you hope these treatments will do for patients?

My hope would be that they would: one, prevent some individuals from going into the ICU; two, for patients who do have to go to the ICU, that they would significantly shorten their stay; and three, they reduce the permanent tissue injury that can have long-term consequences. Any one of those would be great. Hitting all three would be absolutely unbelievable.

Taming the Beast