Fighting Neurodegeneration by Targeting Fossil Viruses in DNA

Fighting Neurodegeneration by Targeting Fossil Viruses in DNA

An estimated 8% of the human genome is comprised of human endogenous retroviruses (HERVs) which are the remnants of ancestral viruses over the past 100 million years that have taken root and integrated into our DNA. HERVs have shaped the diversity of our human genome and participate in the body’s gene activity. 

The components of HERVs that lie deep within our physiology have surprisingly co-evolved with our DNA to benefit our body in some cases, including selected HERV envelope proteins being coopted for pregnancy-related purposes and to provide a protective effect against exogenous infections. However, on a daily basis, HERVs are unable to produce viral proteins, keeping their viral history locked away. 

Unless, of course, the body has an infection. In a pathogenic environment, certain HERVs can become “activated”, producing viral proteins that can trigger immune responses. These immune responses and the viral proteins created by normally suppressed HERVs may provide the missing link between infections and autoimmune diseases like multiple sclerosis (MS). 

GeNeuro, a Switzerland-based company, has taken over three decades of research on HERVs and begun to develop therapeutics that tackle the viral proteins that potentially contribute to neurodegeneration seen in patients with MS, amyotrophic lateral sclerosis (ALS) and even COVID-19. 

Earlier this year, a study led by the Harvard T.H. Chan School of Public Health found that of 801 people with MS who were tested, all but one was infected with Epstein-Barr virus (EBV), a common herpes virus that infects 95% of the population and usually doesn’t cause any symptoms. Of course, not everyone who has been infected with EBV is diagnosed with MS, but GeNeuro’s team believes that HERVs help to explain the pathway from viral infection to autoimmune pathology. 

“The HERV-W was the first HERV protein identified in the early 90s. It took quite some time to understand that the proteins that looked like a virus were not from the environment, but something produced by patients. To this day, you will find the HERV-W proteins in every single brain of MS patients that has been looked at post-mortem.” Jesús Martin-Garcia, chairman and CEO of GeNeuro said in an interview with BioSpace. “You don’t find it in the brains of people who die with Parkinson’s or Alzheimer’s or stroke.” 

The main driver of pathophysiology and symptomology in patients with MS is the destruction of the myelin sheath on neurons by the immune system. Myelin sheaths wrap around the axons of neurons, insulating the cell and promoting the quick and efficient transmission of electrical impulses in the central nervous system. When the myelin sheath is damaged, such as in those with MS, it can cause symptoms including vision loss, numbness and tingling in the limbs, pain, fatigue and memory problems. 

pHERV-W Env is a HERV viral protein that researchers and GeNeuro believe is implicated in MS and is potentially the causal factor of the myelin-degenerating disease. pHERV-W Env has been observed in research studies to activate microglial cells - macrophagic cells that remove damaged neurons - and release certain diffusible factors into aggressive phenotypes which attack myelin. Moreover, pHERV-W Env has also been observed to hamper the remyelination capacity of oligodendrocyte precursor cells, which are cells that work to myelinate the sheaths of neurons. Together, impacting these mechanisms in the brain allow HERVs to proliferate permanent damage.

To combat these damaging impacts, GeNeuro has developed temelimab which neutralizes pHERV-W Env.  

“Phase II studies with temelimab showed that it had a profound effect on the key markers of neurodegeneration as measured by MRI, with a very strong reduction of the atrophy rates of the different compartments of the brain in MS patients, and a preservation of myelin integrity in the different layers of the brain,” Martin-Garcia said.   

Clinical data from GeNeuro’s CHANGE-MS trial and ANGEL-MS extension have shown that after two years of treatment, patients who were treated with temelimab showed evidence of continued improvements in MRI-based neurodegenerative outcomes as compared to the control group and the effects were not driven by an anti-inflammatory pathway, pointing toward the effectiveness of neutralizing HERVs.  

GeNeuro recently shared positive Phase II clinical trial data from its ProTEct-MS clinical study, which followed 41 MS patients who were treated with rituximab, an anti-neuroinflammatory medication, and whose disability was worsening in the absence of relapses. The primary endpoint of the study was met, showing that temelimab had an excellent safety and tolerability profile when administered at the same time as an anti-inflammatory drug. Results also showed that the drug, again, had a favorable impact on key MRI parameters. 

“In autoimmune diseases, the perceived importance of viruses has fluctuated for the last 30 years. The recent Science article stating that EBV causes MS has renewed this interest, but the issue is always the same: if EBV was the direct cause of MS, 95% of us would have MS,” Martin-Garcia pointed out. “You need a mechanism in the middle to explain why this is happening, and we’ve been proposing for many years the biological mechanisms by which viruses can cause autoimmune diseases, by interacting with the viral part of our DNA. There is strong evidence of this interaction in MS, but also in Type 1 Diabetes, Inflammatory psychosis and even in emerging diseases such as Long COVID.”  

To that effect, GeNeuro is also investigating the HERV approach in COVID-19 and ALS. A research study of COVID-19 patients published in April 2021 found that HERV-W ENV was present in all participants and that the level of the expressed viral protein was associated with disease severity. It’s possible that the properties of HERV-W could play a role in the long-term recovery of patients with COVID-19, and GeNeuro is curious to see if temelimab is up to the test of reducing COVID-19 disease outcomes.  

“Long COVID is a big basket with a high diversity of symptoms and many non-exclusive potential causes. One of them obviously being the damage during the acute phase, which the body takes time to recover from. Another possible factor may be that, in some patients, reservoirs of SARS-CoV-2 are still shedding viral proteins, which is why you would see high innate immunity markers in certain Long COVID patients. There’s another potential cause, which is that there is something destabilizing the innate immune system, and HERV-W may be the answer," Martin-Garcia said. "There is today strong evidence that SARS-CoV-2, the virus causing COVID-19, de-represses the expression of HERV-W in susceptible individuals. These pathogenic proteins, which are not found in healthy persons, can be measured in the blood of a high proportion of Long COVID patients, and may explain many of the neuropsychiatric symptoms experienced by these patients." GeNeuro is launching a clinical trial to neutralize these proteins in patients testing positive for them.

A different HERV protein, called p-HERV-K Env, is thought to be implicated in ALS. It has been identified in sporadic ALS patients as causing the degeneration of motor neurons. GeNeuro has entered into a research collaboration with the National Institute of Neurological Disorders and Stroke to develop treatments designed to neutralize p-HERV-K Env in ALS patients.  

There are a host of other diseases that could potentially be treated or mitigated by HERV therapeutics such as Type 1 Diabetes, inflammatory psychosis and chronic inflammatory demyelinating polyneuropathy.   

“The huge potential of this technology is going to bring new solutions against autoimmune diseases and in particular, neurodegeneration. It’s an incredibly important field, and I’m happy and proud to be contributing to it,” Martin-Garcia said.  

Published: May 19, 2022

https://www.biospace.com/

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