Ancient virus implicated in MND

New research is set to explore the role of endogenous retroviruses, which first emerged during the early Palaeozoic Era, 460 to 550 million years ago, and the development of Motor Neuron Disease (MND) in the modern-day population.

Retroviruses are enveloped RNA viruses that depend on host for survival and reproduction, which evolved alongside vertebrates, integrating with their host to the point where they become embedded in the germline and can be potentially passed on to the host’s offspring. 

More than 8% of the modern human genome is derived from human endogenous retroviruses (HERVs) which have copied and pasted themselves into the DNA over millennia, with large segments of their original code becoming mutated, partially deleted or epigenetically silenced. 

However, aging, cancer, infections with modern viruses and inflammation can dampen this epigenetic control, resulting in the renewed transcription of the potentially mutated segments from the ancient virus, and with more 40,0000 HERV-derived sequences identified so far, the link with MND captured the attention of Australian researchers.  

Recent findings have demonstrated many implications of a role of viruses and endogenous retroviruses in neurological diseases such as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's. 

A new cutting-edge project under the leadership of Flinders University Health and Medical Research (FHMRI) Associate Professor, Mary-Louise Rogers, will test if one of these ancient viruses may cause MND and, whether targeted therapy could help with the development of more effective treatments for the disease. 

“There are still huge gaps in our understanding of what causes motor neurone disease, and in the development of effective treatment options. With no known cure, we urgently need to gain a better understanding of this disease so we can develop more successful therapies and improve patient outcomes,” Associate Professor Rogers explained. 

“Our cutting-edge project will use genomic and cellular tools to map out how endogenous retroviral remnants may alter cells and cause motor neurone disease. We will then test whether antisense therapy targeted to an endogenous retroviral protein can be used to successfully treat MND.” 

MND - also known as Amyotrophic Lateral Sclerosis (ALS) in other parts of the world - is a fatal neurological condition, in which the nerve cells controlling the muscles that enable movement, speech, breathing and swallowing undergo degeneration and die.  

One in 300 Australians will be diagnosed with MND during their lifetime, with a reliable diagnosis only occurring late during disease progression, resulting in irreversible nerve damage. The average life expectancy is only 27 months from diagnosis in Australia. 

In early 2016 scientists at the NIH showed that brain samples from MND patients had higher than normal levels of mRNA encoded by genes of the human endogenous retrovirus K (HERV-K). 

A protein encoded by a critical HERV-K gene, called env, was found in brain samples from MND patients but not from healthy individuals, and the team also demonstrated that activation of HERV-K genes killed healthy human neurons grown in petri dishes.  

The team from the College of Medicine and Public Health has received almost $1 million in funding from leading Australian funding organisation FightMND to support their research, which will confirm not only if a HERV causes MND, but whether antisense therapies against a retroviral protein could help fight the disease. 

“Antisense therapy is an approach to fighting diseases using short DNA-like molecules called antisense oligonucleotides, which has emerged as an exciting and promising strategy for the treatment of various neurodegenerative and neuromuscular disorders,” Associate Professor Rogers explained.  

“Our results may be able to help the current Lighthouse Trial that is testing anti-retroviral therapy and could be significant in the future development of treatments.” 

The Lighthouse project, a collaborative effort between Macquarie University, Westmead Hospital, Calvary Health Care Bethlehem, and the University of Sydney’s Brain and Mind Centre (headed by Professor Julian Gold), is the first clinical trial in the world conducted with modern combination antiretroviral therapy to improve disease progression in patients with MND. 

Phase 2 of the trial has already showed that a drug called Triumeq, previously used to treat HIV, may slow disease progression in people living with MND.