Children born without immune defenses cured thanks to the AIDS virus

Because they were born without immune defenses, they were condemned to spend their lives in a bubble, away from the world and its microbes. Now, these eight little boys with severe combined immunodeficiency – a rare genetic disorder – are eligible for a normal life. In the United States, doctors at two children's hospitals have managed to fully rebuild a functional immune system using a combination therapy of gene therapy and chemotherapy. A world first described in detail on April 18 in the New England Journal of Medicine .

One month after receiving treatment, 7 of the 8 children had left the hospital. Only one had to receive a second dose. And after just over a year of follow-up, all the children are doing well. "These patients (…) respond to vaccines and have an immune system that allows them to make all the immune cells they need to protect themselves from infections," said Dr. Ewelina Mamcarz, co-author of the study and bone marrow transplant physician and cell therapy at St. Jude Children's Hospital in Memphis, United States. "Although longer follow-up is needed to evaluate the late effects of treatment, these results suggest that most patients treated with this gene therapy will develop a lasting and complete immune response with no side effects," said Prof. Dr. Mort Cowan , a pediatrician at Benioff Children's Hospital at the University of California, San Francisco, where 4 of 8 children were treated.

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What is the disease?

"This disease is due to the lack of a structure on the surface of the cells of the immune system. Without that, the cells are like blind. "

Anne Galy, Research Director at Inserm / Genethon

Severe combined immunodeficiency, also known as "baby bubble disease", is very rare: it affects only one birth out of 200,000 every year, exclusively boys. "This is the most common form of immune deficiency," says Anne Galy, director of research at Inserm / Genethon. "It's due to the lack of a structure on the surface of the cells of the immune system. Without this, the cells are like blind: they can not move, do not proliferate, do not activate. " This deficit is due to an error in the genetic code: in the absence of the gene coding this indispensable structure, the cells are unable to manufacture it.

Children born with this syndrome therefore have an immune system but it is like extinct. "In the beginning, infants look healthy, but very quickly they catch infections that put their lives at risk," says Anne Galy. "To protect them from the environment, they are put in sterile bubbles because they absolutely can not defend against microbial infections". If nothing is done, their life expectancy is very limited.

For the time being, bone marrow transplantation – the seat of the production of immune system cells – remains the preferred treatment, although it is very restrictive (taking immunosuppressive drugs for life, developing cancers). But for children who do not have a compatible donor around them, this option is unthinkable because of an almost inevitable risk of transplant rejection. In 1999, a pioneering Franco-British team carried out the first gene therapy treatment.

The concept: to take stem cells (which are not yet differentiated) from the patient to inject the missing gene into the laboratory. "The advantage is that there is no risk of rejection since it is the patient's cells," says Anne Galy. But among the 19 young patients included in the first clinical trial, many subsequently developed leukemia because of treatment. And, according to the researcher, the effects of this gene therapy eventually run out after "15 to 20 years". It needed to be improved.

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Chemotherapy and AIDS viruses

That's what the teams at St. Jude Children's Hospital did. The novelty is that doctors have administered chemotherapy in addition to gene therapy. This treatment, usually used against cancer, aims here to remove all the cells of the patient's bone marrow. "Until now, we did not do it because we thought it was to make him take an additional risk," says Anne Galy. "If you remove your bone marrow and then the transplant does not take, it permanently loses its immune system." In fact, researchers have found that chemotherapy is the only way to transplant the entire immune system in a sustainable way.

"The advantage of HIV is that it makes it very easy to insert a copy of the normal gene into the DNA of the cells."

Anne Galy, research director at Inserm / Genethon.

Another peculiarity – even if it is not a first – doctors used the human immunodeficiency virus (HIV) to transport the gene to the heart of cells. "The advantage of HIV is that it makes it very easy to insert a copy of the normal gene into the DNA of cells," explains Anne Galy. But beware, these are not real AIDS viruses. "They are synthesized in the laboratory, as are drugs, but are not infectious. We only keep the properties that interest us. It's a bit like a shell, "says the researcher. These viral vectors have been used for a long time in gene therapy, not only to treat immune deficiencies.

In practice, American doctors put the patient's stem cells in contact with these small viral shells carrying the missing gene, before allowing them to develop in the laboratory. At the same time, they made their way to the patient by administering chemotherapy before injecting his own genetically modified cells.

For now, these therapies are only done in the context of clinical trials. This study brings a new proof of effectiveness of the concept. "From now on, it is necessary that it leaves the academic field and that the industrialists seize it. It has to be licensed drugs that may be available in hospitals, "says Anne Galy. For their part, the authors of the study "hope that this therapy, which includes several novelties, will serve as a basis for the development of gene therapies to treat other devastating blood diseases".