“On the Edge of Personalized Medicine”: Dr. Athanasopoulos of ANU explains the discovery of the lupus gene

Lupus, like many autoimmune diseases, can slip under your radar if it does not affect your family.

But for an estimated 1 in 1,000 affected Australians, reports of a scientific discovery that paves the way for targeted treatment are music to their ears.

Lupus causes the immune system of millions of people around the world to attack their own cells. It manifests itself in a variety of ways, from skin rashes, joint pain and fatigue to heart, lung or kidney problems and other serious cases.

“Butterfly rash” on the face and nose is one of the most common symptoms of lupus (experienced by about one in 5 patients). The symptoms of lupus vary from person to person, can vary over time and can range from mild to severe with even potentially fatal complications in extreme cases. Photo: healthdirect.gov.au

Vicki Athanasopoulos of the Australian National University’s John Curtin School of Medical Research was one of two supervisors at a study that identified a gene driver for the disease, called TLR7.

It is “the first time we have evidence of the cause of lupus in humans,” he says Neos Cosmos.

And there are hopes that the study could have implications for the treatment of multiple autoimmune diseases and also contribute to an understanding of viral mechanisms, including COVID-19.

A five-year study led by ANU researchers was conducted by a team of more than 40 international contributors from the UK and Spain to the US and China.

Gamechanger? A rare genetic mutation in a Spanish girl

Dr. Athanasopoulos says he shares glimpses of a breakthrough scientific process triggered by patients:

“One of our associates was a clinician in Spain with this young patient, Gabriela, who had an early and severe lupus; she was about 7 years old at the time of diagnosis. So we got blood from her and sequenced her DNA to find out what mutations can contribute to her illness. ”

TLR7 was one of the genes that stood out as a candidate, due to the role it plays in helping the immune system recognize viruses and the nature of the mutation it represented in Gabriella’s case.

“She had what we call a de novo mutation, which means her parents didn’t have it, it was the first in a girl,” says Dr. Athanasopoulos about genetic variation.

The variation that was responsible for the attack relaxed on some of the patient’s main organs, including her heart and kidneys.

“The evidence came when we took the same mutation we found in a young girl and introduced it into an animal model and saw a similar disease in mice. This showed us that the TLR7 mutation causes lupus.

Lecturer Dr. Vicki Athanasopoulos (C) with researcher Dr. Hao (Howard) Wang and Chief Technical Officer Jean Cappell (R) at the ANU John Curtin School of Medical Research (JCSMR). Photo: Tracey Nearmy / ANU.

The study may also help explain the “gender bias” of lupus, which is significantly higher in women.

“Interestingly, TLR7 is located on the X chromosome, so we think that may be one of the reasons why women are, say, nine times more affected by lupus than men,” says Dr. Athanasopoulos.

The effect of the hyperactive TLRF7 gene, he explains, can be twofold in women because they have two X chromosomes, unlike men who have only one.

The culprit was found. What now?

Although not every lupus patient has an overactivated variant of TLR7, confirmation that it is a lupus gene paves the way for the development of new targeted therapies.

“If you can identify which gene is involved, you can identify a path that you can then try and either transform current drugs or develop new ones to try to treat and specifically target that gene pathway,” explains Dr. Athanasopoulos.

Photo: Tracey Nearmy / ANU

Initial trials of new drug therapies have already begun, and one of the team’s next steps will be to explore the potential application of their findings to conditions other than lupus.

“We think the TLR7 pathway may be hyperactive in other autoimmune diseases.” And we’re trying to prove or disprove whether that’s really the case. “

The prospect of a better understanding of coronavirus and other viruses is also one of the benefits of the new findings, thanks to the function of the TLRF7 receptor in virus detection.

Dr. Athanasopoulos cites at least two studies published during the pandemic that show that some patients have experienced more severe COVID due to mutations that cause inactivation of their TLR7 receptor.

“So it’s like balancing.” You do not want TLRF7 too active [the mutation found causing lupus] and you don’t want too little because you have to be able to fight infections, ”he explains.

Therapeutics tailored to patients

Genetic nuances may be crucial in the development of targeted therapies.

“Part of this is knowing which paths to focus on, understanding the genetics and molecular basis of the disease,” says Dr. Athanasopoulos.

And the second generation of Greek Australians has the expertise to support this mission.

Vicki Athanasopoulos graduated from university with her sister Helen Louras, their late father George and mother Anastasia. Both parents come from Kalamata, Greece, and migrated to Australia in the 1960s. Photo: Vicki Athanasopoulos

“I’m a molecular biologist, so I’m interested in how molecules work and the roughest details involved.”

Her legacy is attributed as a less common weapon in her arsenal as a scientist, and her knowledge of Greek fits in a medical dictionary.

“In Melbourne, you hear people speak Greek as you walk down the street. Sometimes I miss it. “Vicki Athanasopoulos has settled in Canberra and visits Sister Helen Louras and her mother in Melbourne whenever possible. Here are the two sisters pictured on Vicki Athanasopoulos’ graduation day. Photo: Delivered

“It simply came to my notice then. So, when you come across a complex medical term – because I didn’t do medicine, but I did science – you can somehow break down the word and say, “OK, I think I know what that means.” And the strange thing is that when I see such a Greek word, I can’t pronounce it in English. I have to say it in Greek. “

Asked about her aspirations and the aspirations of her team to offer some relief to lupus sufferers with new therapies, Dr. Athanasopoulos explains that the daunting task is difficult for a condition that cannot be cured and for which treatment options are minimal.

“Lupus is very complicated.” You have about 11 different symptoms and you only need four of these markers to be characterized by lupus. And it can vary in the severity and types of cells that are affected and the organs that are affected. “

Photo: Tracey Nearmy / ANU

However, after identifying the gene causing lupus, the outlook is optimistic.

“By understanding the cause of the disease, you can better understand how to treat it.

“We are now working to improve the process of screening for mutations that we find in patients’ DNA so that we can show which ones are likely to cause and cause disease and which are not.

[…] I think we are on the brink of personalized medicine, where we can, you know, target a specific patient or group of patients more effectively, because we know that this is what has gone wrong in this group of patients. And these are the right drugs to treat them. “


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