In this video, Rajiv Ratan, MD, PhD, Chief Executive Officer, Burke Neurological Institute; Associate Dean; Burke Professor of Neurology and Neuroscience; Professor of Neuroscience, Weill Cornell Medicine, New York, New York, discusses his presentation given at the 146^th Annual Meeting of the American Neurological Association titled “Harnessing Hypoxic Adaptation to Interdict Ferroptosis and Treat Neurological Diseases.”

Read the Transcript:

Dr Ratan:  Hi. My name is Raj Ratan. I'm the director and CEO of the Burke Neurological Institute, and I'm a professor of neurology and neuroscience at Weill Cornell Medicine. My talk at the ANA this year focused on a long-standing interest in my lab that relates to hypoxic adaptation, and it was in the session Hypoxic and Anoxic Injury (in the CNS).

The story starts not with oxygen, but rather with a trace metal called iron. As many of you may be aware of the dysregulation of iron has been observed in almost every pathological condition.

When people section the brain from those who have died from different neurological conditions, almost uniformly, we see this homeostasis of proteins that are involved in iron regulation. The $64,000 question, obviously, is, are these changes in iron a tombstone, or are they a cause of the disease?

The best evidence that they might be a cause comes from animal models, where small molecule drugs, that cheli-iron actually have shown a remarkable neuroprotective effects in models of stroke, in models of Parkinson's disease, in models of Alzheimer's disease, and multiple sclerosis, and I could go on and on.

Now, the challenge in being able to translate iron chelators to humans has been that they not only have these beneficial effects, but about 30% of the enzymes in our cells and our neurons are iron-dependent. It's a component that appears to be involved in pathology but is also very important for the normal physiology of the brain.

My lab has been interested in figuring out what's the target for iron chelators. If we can figure out that target, can we develop better drugs?

My presentation focused on this serendipitous observation that we made when I was a postdoc at Hopkins in the early '90s, that iron chelators appeared to be able to harness an elegant, adaptive transcriptional system that exists in all the cells of our body when they become hypoxic. Under normal conditions, oxygen levels are adequate. Everything's fine in our cells.

In response to hypoxia, for instance, if someone has lung problems or if someone impedes blood flow to the brain, like in a stroke, oxygen levels fall. Even if one travels to a high altitude, like going to Mt. Everest, oxygen levels fall. This triggers a really elegant adaptive response that involves a single protein, a transcription factor called Hypoxia-Inducible Factor-1.

The stability of this transcription factor, in other words, its levels are determined by a group of enzymes called the HIF prolyl hydroxylases. These enzymes are iron, oxygen, and 2-oxoglutarate dependent. My lab has been pursuing the idea that iron chelators inhibit these enzymes. They fool the body into thinking it's hypoxic.

What happens is this transcription factor of protein is stabilized. It then moves into the nucleus with its partner, and it up-regulates all the genes that you would want to be up-regulated if the body were hypoxic. Erythropoietin, which actually not only is neuroprotective but can increase red blood cells that increase oxygen delivery to the brain.

Vascular endothelial growth factor, which increases the number of blood vessels in the brain, would also similarly increase nutrients like glucose and oxygen. Then glycolytic enzymes, which shift the ability of neurons to require oxygen for ATP or energy generation away from the mitochondria to other forms.

In order to develop a drug, what we did is we developed a cell-based screen, and screened 85,000 compounds, and identified a seven set of pharmacophores that we could choose from to be able to have as our lead compound. We settled on a drug that we called Adaptaquin because it drives the adaptive response to hypoxia in all the cells of our body and allows us to turn it on whenever we want. It's got the quin because it's a hydroxyquinoline backbone.

I described in my talk the fact that we were able to validate this drug affects the enzymes that we wanted it to, the HIF prolyl hydroxylases. We did that in collaboration with a group at Oxford, Chris Schofield and his group.

We used a nifty technique in the bioluminescence imaging, to be able to show that the drug gets into the brain and turns on the adaptive response in the brain. There, what we found is that the optimal concentration of the drug to be able to affect this adaptive response was 30 milligrams per kilogram.

We then tested the ability of this drug to work in a whole host of different disease models, and we found that it protects against hemorrhagic stroke, ischemic stroke, Parkinson disease, traumatic brain injury, and amazingly, a genetic cause of retinal degeneration.

The overall conclusion is that if you can figure out how the brain is sensing stress at a molecular level and then you can convert that into an adaptive genetic response, you're then able to harness that response with drugs that then have this remarkable ability to protect the brain.

It gives rise to the conclusion that disease may be a failure of these endogenous adaptive mechanisms that have to be triggered robustly. That failure can be overcome through drugs like Adaptaquin.

The other advantage of this approach is that by using a response that's evolved over millions of years, and that involves more than 100 genes, you're able to get with a single drug maybe the benefit of what 100 drugs might have to accomplish otherwise.

This allows us to think about a rational therapeutic mechanisms that might address the heterogeneity that exists in humans that often makes drugs fail like people have different comorbidities and people have different genetics. The same disease may present in a variety of different ways.

By activating this large program, we're hoping that this therapeutic approach will be successful as we move it to humans.