Motor neuron disease inflammation trigger discovered

In collaboration with colleagues at the Walter and Eliza Hall Institute (WEHI) and the University of Melbourne, Hudson Institute scientists have revealed how inflammation in motor neuron disease (MND) is caused, which could be the first step towards a new treatment.

Dr Michael Gantier from the Nucleic Acids and Innate Immunity Research Group at Hudson Institute
Dr Michael Gantier

The research team pinpointed the molecules involved in the inflammatory pathway to work towards a potential treatment that could slow the progression of MND – offering hope to people with the incurable and debilitating illness.

The scientists found that by blocking an immune sensor called STING, they could dramatically prevent inflammation in patient motor neurons (the cells destroyed by MND), promoting motor neuron survival. This discovery lays the foundations for a potential new class of drugs for people with neurodegenerative disorders, including motor neuron disease.

The discovery, published in Cell, was led by Walter and Eliza Hall Institute researchers Associate Professor Seth Masters and Dr Alan Yu, with colleagues from the University of Melbourne and Hudson Institute of Medical Research scientist Dr Michael Gantier.

Co-author of the study Dr Gantier said, “The STING immune sensor and its inflammatory pathway are normally involved in protection against viruses and bacteria, but they can also be activated in damaged cells.

“Our work discovered how build-up of a protein called TDP-43 – which occurs in most people with motor neuron disease – drives activation of the STING pathway. This results in persistent brain inflammation, which has devastating effects on brain function.

“The study also demonstrates that blocking the STING immune sensor with a drug-like compound can halt the progression of MND. This opens the door for the development of therapies to help slow the progression of other neurodegenerative diseases where the STING inflammatory pathway is involved.

“Importantly, these findings further indicate that the STING inflammatory pathway is probably a key driver of other neurodegenerative diseases, as recently suggested for Parkinson’s disease.”

Halting the inflammatory response in motor neuron disease

Motor neuron disease is an incurable condition in which the nerve cells controlling the muscles that enable us to move, speak, swallow and breathe, fail to work. One in 10,000 people in Australia will be diagnosed with MND in their lifetime and the average life expectancy from diagnosis is just two years.

Most people suffering from MND have an accumulation of a protein called TDP-43 within cells of the central nervous system. This build-up is associated with an inflammatory response that causes major symptoms of MND.

WEHI researchers investigated how the disease-causing inflammation is triggered in MND, said A/Prof Masters. “This unexpectedly identified that an immune sensor called STING is activated downstream of TDP-43. Fortuitously, our team had already studied the role of STING in other inflammatory diseases and are now working out how to block it.”

The team then used new inhibitors – drug-like compounds – to block different components of this inflammatory pathway.

“Using cells from patients with MND that we can turn into motor neurons in a dish, we showed that blocking STING dramatically prevented inflammation and kept the cells alive longer. This is an exciting first step before taking these inhibitors into the clinic for treatment for MND.”

Vital first step towards a motor neuron disease treatment

A/Prof Masters said his research had also established activation of STING in people who had passed away due to MND.

“We are now aiming to validate a biomarker of the pathway earlier in the disease progression. Once this neuroinflammatory biomarker is validated, we will better understand which patients will benefit the most from treatments targeting the pathway,” he said.

“With this knowledge, there is the potential to develop a treatment for patients with MND.

“Interestingly, our preclinical models suggest that although the anti-inflammatory drugs that inhibit STING did not prevent disease onset, they did slow the degenerative progression of disease.”

Hope for people with neurodegenerative disorders

A/Prof Masters said this discovery offered hope for people diagnosed with the debilitating condition.

“We are hopeful this research could lead to a treatment for people with established MND, who currently have very few treatment options and a life expectancy post diagnosis of just two to five years,” he said.

“While it isn’t a cure, we hope it might extend life expectancy and dramatically improve the quality of life for people diagnosed with MND.”

Looking to the future

Dr Michael Gantier and his laboratory have recently identified several pre-clinical and clinic-ready drugs that can block the STING inflammatory pathway. His team is now starting to investigate, with collaborators including A/Prof Masters, whether these drugs can be used in various contexts where the STING pathway is a key driver of the disease, including chronic obstructive pulmonary disease, sepsis, fatty liver disease, auto-immune diseases like systemic lupus, in addition to MND.

These studies have the capacity to be rapidly translated into effective treatment options for the thousands of people suffering with MND, and these other diseases.

Funders Australian National Health and Medical Research Council, veski, HHMI-Wellcome Trust, the Sylvia and Charles Viertel Foundation (SLM), the Australian Research Council, Fellowship Fonds de recherche du Québec-Santé, the WEHI Centenary Fellowship and Ormond College’s Thwaites Gutch Fellowship in Physiology, the Motor Neurone Disease Research Institute of Australia, the Australian Phenomics Network, the Ian Potter Centre for Genomics and Personalized Medicine and the Victorian Government.

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