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Gabriela may have been the person who changed the treatment of lupus, an autoimmune disease for which there are currently no therapies.
In a study published in Nature and coordinated by Carola Vinuesa, principal investigator at the Center for Personalized Immunology in Australia, and now at the Francis Crick Institute where she directs a laboratory to better understand the mechanisms that cause diseases that occur after key mutations, the complete genome was sequenced in the DNA of Gabriela, a Spanish girl who was diagnosed with severe lupus when she was 7 years old. Such a severe case with early onset of symptoms is rare and indicates a single genetic cause, the researchers explain.
In this way, this team has identified mutations of ADN in a gene that detects viral RNAas a cause of lupus.
The finding, they write, paves the way for the development of new treatments.
Vinuesa clarifies that it is not the first gene, there have been more monogenic cases, but “we think it is important because it is a very important hub because many signaling pathways branch out from it and because in our work it contributes the definitive proof of causality, with which it is now known that the activation of TLR7 is pathogenic».
The study has shown that TRL7 regulates quite a few aspects of the immune system that all contribute to causing lupus.
Lupus is a disease autoimmune that causes inflammation in organs and joints, affects movement and skin, and causes fatigue. In severe cases, symptoms can be debilitating and complications can be fatal.
There is no cure for the disease, which affects more than 40,000 people in Spain, of which 90% are women. Furthermore, current treatments are predominantly immunosuppressants that work by reducing the immune system to relieve symptoms.
In their genetic analysis, conducted at the Australian National University Center for Personalized Immunology, they found a single point mutation in the TLR7 gene.
Reviewing other US references and the CPersonalized Immunology Center of China and Australia (CACPI) at the Renji Hospital in Shanghai, they identified other cases of severe lupus in which this gene was also mutated.
To confirm that the mutation causes lupus, explains Vinuesa, we used the CRISPR gene editing technique to introduce it into mice. These mice developed the disease and showed similar symptoms, providing evidence that the TLR7 mutation was the cause. “The mouse model and the mutation were named ‘kika’ by Gabriela, the young woman at the center of this discovery,” she notes.
“It has been a great challenge to find effective treatments for lupus and the immune system. Immunosuppressants currently in use can have serious side effects and leave patients more susceptible to infection. There has only been a single new treatment approved by the FDA (US health authorities) in approximately the last 60 years,” says Vinuesa.
Vinuesa emphasizes that this is “the first time that it has been shown that a TLR7 mutation causes lupus, which provides clear evidence of one of the ways this disease can arise.”
Although, as Nan Shen, co-director of CACPI acknowledges, it is possible that only a small number of people with lupus have variants in TLR7, “we know that many patients have signs of hyperactivity in the TLR7 pathway. By confirming a causal link between the gene mutation and the disease, we can start looking for more effective treatments.”
The mutation the researchers identified causes the TLR7 protein to bind more easily to a nucleic acid component called guanosine and become more active. This increases the sensitivity of the immune cell, making it more likely to incorrectly identify healthy tissue as foreign or damaged and to mount an attack against it.
Although the study has been done in the case of Gabrielawhich is rare, continues Vinuesa, «we think that our data may be valid in other patients who do not have this mutation, in patients with less severe lupus».
Interestingly, other studies have shown that mutations that cause TLR7 to become less active are associated with some cases of severe Covid-19 infection, highlighting the delicate balance of a healthy immune system.
Vinuesa says the study may also help explain why lupus is about 10 times more common in women than in men.
Because TLR7 is located on the X chromosome, females have two copies of the gene while males only have one. Usually in women, one of the X chromosomes it is inactive, but in this section of the chromosome, silencing of the second copy is usually incomplete. “This means that women with a mutation in this gene can have two functional copies.”
A key figure in this study is Carmen de Lucas Collantes, from the Niño Jesús University Children’s Hospital and co-author of the study. «Collantes sees very severe cases of lupus and it was she who sent me the DNA of her complicated patients because she knows that we are studying this line. One of her samples was Gabriela’s and there we started working with her to design this model».
“The identification of TLR7 as the cause of lupus in this unusually severe case ended a diagnostic odyssey and provides hope for more targeted therapies for Gabriela and other lupus patients likely to benefit from this discovery,” Collantes said.
The researchers are now working with pharmaceutical companies to explore the development or repurposing of existing treatments, which target the TLR7 gene. And they hope that targeting this gene could also help patients with related conditions.
Vinuesa adds that other systemic autoimmune diseases, such as rheumatoid arthritis and dermatomyositis, “fit into the same broad family as lupus. Thus, TLR7 may also play a role in these conditions.”
TLR7 inhibitors have already been developed for other diseases, but “based on our data, Pharmaceutical companies interested in this line of research and in our mouse model with the Gabriela mutation have contacted us. Vinuesa points out. It probably won’t take that long, because there are some already designed, and they are easy inhibitors to design. I’m optimistic, we don’t have to start from scratch.”
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