Unraveling the Roots of ALS Through Reactivation of HERVs and Antibody Levels

Avindra Nath, MD

Some of the difficulties with designing successful therapies for amyotrophic lateral sclerosis (ALS) have come from identifying sustainable targets that focus on the root of the disease. As researchers continue to search for answers, 2 recently published pieces of work point to a potential new pathway for treating a sporadic form of the disease. Part of a collaborative effort between the National Institute of Neurological Disorders and Stroke (NINDS) and the Switzerland-Based biotechnology company GeNeuro Inc, the efforts assessed DNA sequences from ancient retroviruses, referred to as human endogenous retroviruses (HERVs) and their role in ALS.

Thought to be typically dormant, the reactivation of these HERVs could have an impact on the development of neurodegenerative diseases. The first paper showed that HERV-K envelope, a specific protein produced by HERV located in the cerebrospinal fluid of patients with ALS, is toxic when added to neurons grown in laboratory dishes.¹ Additionally, these toxic effects were reduced when the investigators added a synthetic antibody specifically designed to recognized HERV-K envelope. Following those findings, a second paper highlighted that higher levels of antibodies against HERV-K envelope observed in patients with ALS suggests a correlation between antibody levels and overall survival.²

Avindra Nath, MD, clinical director, NINDS, and senior investigator for both papers, sat down with NeurologyLive® to provide more insight on the findings and what they mean for the clinical community. He discussed the complex nature of the data, and why the protective response of antibodies could become a potential therapeutic target for ALS in the coming future.

NeurologyLive^®: What should the clinical community know about these recent findings?

Avindra Nath, MD: Most people have probably never heard of HERVs. This is an acronym that stands for human endogenous—within our system—retroviruses. The most common retrovirus that most people know about is HIV, but apparently, HIV-like sequences are present in the human genome, and we've had them for millions of years. We've acquired them over millions of years, and that's how most human evolution takes place. It’s through acquisition of retroviral sequences. Now, we think of HIV as spreading from person to person. These HERVs get incorporated into the genome, and they've been there for so long, so they mutate. They no longer can form a complete virus, but they can still form RNA and protein, and they're very important in early development. But once the organs are formed, they shut down. You don't really need them any longer.

In evolution, the human brain is formed already in the brain, all the neurons are differentiated, and you want them to shut down; however, they can get reactivated, and they can get reactivated as we get older, or to other circumstances that can lead to their activation. If they do, they can do bad things. Let's say they get activated in a breast cell or plastic cell, they can actually push them to develop cancer, because they push them to divide. They were important in early embryogenesis, they were making cells divide, but if you make cells divide in an adult, you might cause cancer. In the neurons, if you activate these things, you cannot push the neuron to divide. Because the neuron starts in your head and goes all the way down to your leg, so if you try to push them to divide, it's just going to die, and you can end up with a neurodegenerative disease.

The same thing that is so important in our own survival as humans, and so important in embryogenesis, can also lead to our own demise, ultimately. The laws of nature are very simple, we just make them very complicated. But basically, that's what it is. We got interested in looking at these HERVs because we found that they can get activated in brains in patients with ALS. But those were autopsy tissues, and we published a series of papers on that. Now, we wanted to try and study whether we see if these things are activated in patients who have ALS while they're still alive, and how does it affect the progression of the disease?

In the first paper here, we looked for the protein that is found by the envelope of the virus—just like with the COVID virus, you have the spike protein, everybody knows the spike protein. In retroviruses, you have the envelope protein on the outside, and all the viruses are going to interact with other cells through the protein that's outside. We said, “OK, let's look and see if we can find this envelope protein.” With the help of our collaborators, we developed an assay, whereby we could measure the protein, and we found that in spinal fluid, you see significant amounts of protein in patients with ALS that were not in healthy controls. We put the protein on neurons to see what it does, and we found it’s toxic. We knew from working with HIV for many years that the envelope protein of HIV is also neurotoxin, so that's why we homed into the envelope protein. We had the assays in our lab found that it is toxic, and that if you were to take an antibody against the protein, you can prevent it. The next thing we observed was if patients with ALS have antibodies to this protein or not. It turns out that people do, and it makes sense because if they were important in early embryogenesis, and they got shut down, the thymus may not have seen it. If it's not been seen, then if you reactivate it, you're going to drop an immune response against it.

What we found is that, yes, they have an immune response. They have an immune response in particular epitopes. Some healthy individuals may also have it, but when you look at patients with ALS, they have a lot of antibodies against many different regions of the envelope protein. We mapped all those unique regions and looked at what happens over a period of time if you look at them at different ages or different progressions of the disease. What we found is that as the disease advances, the antibodies go down, but the RNA goes up. You're getting more virus production, but the antibody levels are going down. That made us think that maybe the antibodies are good for you, and that's a totally different way of conceptually thinking of autoimmune syndrome. People who study autoimmune say if you have any antibodies against any cell in your body, it's bad. What we're showing for the first time here, is these antibodies directed against HERVs that are coded by a human genome are good for you. One might think is an implication of this is that maybe we need to replace these antibodies and see if that will help the progression of the disease. These are the major observations here in this in these two papers.

Do these findings complicate or simplify our understanding of ALS?

You could look at it either way. The way I look at it is, the more you dig into a disease, the more complicated it will appear. But once you start unraveling these things, you come up with very important nuggets. We're trying to unravel ALS and what we're discovering is that there's an opportunity for developing new biomarkers, there's an opportunity for looking at a whole area of the human genome that's never been looked at in the context of ALS and other neurodegenerative diseases. There are opportunities for developing new diagnostics and new therapeutics targeting these things. I think it opens up a new area of research in the field.

Transcript edited for clarity.

REFERENCES
1. Steiner JP, Bachani M, Malik N, et al. Human endogenous retrovirus K envelop in spinal fluid of amyotrophic lateral sclerosis. Annals of Neurol. Published July 8, 2022. doi:10.1002/ana.26452
2. Garcia-Montojo M, Simula ER, Fathi S, et al. antibody response to HML-2 may be protective in amyotrophic lateral sclerosis. Annals of Neurol. Published online July 31, 2022. doi:10.1002/ana.26466