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Infants born with an extremely rare and sometimes life-threatening genetic disease, sometimes known as "bubble boy disease," have been effectively treated with gene therapy developed by American scientists.
Children with this disorder, called severe combined immunodeficiency or SCID, are born without a functioning immune system, which means that they have little or no means to protect themselves from infection.
Decades ago, SCID patients had to be kept in special plastic chambers, which sparked public fascination with the disease and several Hollywood bubble boy movies.
In the absence of treatment, patients with SCID-X1 – the most common type of SCID – rarely live after their first birthday. A simple infection like a cold can be fatal.
This disorder, which affects about one in 100,000 newborns, is due to a mutation in the gene that produces a protein that is essential for normal immune function.
Only boys are affected, due to the inherited structure of the defective gene.
In a study of eight children in whom SCID-X1 had been diagnosed, doctors took bone marrow from their patients and inserted a corrected copy of their mutated gene (the one that caused them low immunity) into the blood. DNA from their blood stem cells.
In just a few months of treatment, the 10 children have all produced functional immune cells for the first time, said Ewelina Mamcarz, a pediatric hematologist-oncologist at the St Jude Children's Research Hospital and co-author of the Pediatric Research Institute. a study published today in the New England Journal of Medicine.
"These patients are young children, who respond to vaccines and have an immune system that allows them to protect all the immune cells they need … a first for patients with SCID-X1", said Dr. Mamcarz.
Until now, the best treatment for SCID-X1 has been a stem cell transplant from a twin donor tissue. But only one fifth of babies have such donors.
The rest must rely on a stem cell transplant from another donor, which is not always possible and, where appropriate, is less likely to cure SCID-X1 and more likely to lead to serious complications .
How does gene therapy work
Genes, made of DNA, are the model of our body.
Each human cell contains about 25,000 genes and the DNA sequence of each gene contains instructions on the construction of certain enzymes and proteins, each having a specific work.
If a person is born with a defective, missing, or mutated gene, they can develop a disease.
The idea of gene therapy is to introduce, delete or modify the genetic material of cells to treat a specific disease.
For example, a bad gene can be replaced by one that is healthy, a new gene can be added to fulfill the defective or missing gene function, or a problematic gene can be disabled.
To add a healthy copy of a gene into the genome of a person, scientists use what is called a vector. Viruses are often used as vectors because they infect and block the DNA in cells.
For gene therapy, the infectious part of the virus is removed and the healthy gene gets in the way when the virus enters the cell without making the patient sick.
Using this method in the SCID-X1 trial, doctors took the baby's bone marrow to collect stem cells, which were frozen, tested, and infected with a virus carrying a working copy of the defective gene.
"Before reinjection of gene-corrected blood stem cells to patients, infants received two days of low-dose busulfan – a chemotherapy agent commonly used in bone marrow transplants to make room for donor stem cells to develop, "Dr. Mamcarz said.
After 10 days, the cells were returned to the baby's body with a virus carrying the corrected gene, where they were able to proliferate and produce healthy immune cells.
New treatment builds on previous trials
In the three months following treatment, T and NK cells (immune cells helping to fight infections) and B cells (which produce antibodies) were present in the blood of all but one of the babies, who need to be treated. a second dose of gene therapy.
"The results have been truly remarkable for our patients," said Dr. Mamcarz.
Importantly, she added, patients did not require continuous treatment, unlike other treatments, and no patient had developed leukemia – a side effect of previous trials.
In the early 2000s, gene therapy trials for SCID-X1 were temporarily discontinued after several patients developed cancer. Researchers have since looked for ways to perform gene therapy without these side effects.
Stephen Gottschalk, also of St Jude Children's Research Hospital and co-author of the study, said the virus used in this new trial was specifically designed to include "insulators" that prevented the gene therapy to inadvertently substitute for carcinogenic genes in the patient's stem cells.
"Previous gene therapy efforts did not have these insulators that inadvertently caused leukemia by activating the genes next to the inserted vector," said Professor Gottschalk.
"In the original studies, leukemia had developed after about 12 to 15 months." So far, there is no evidence of a pre-existing stage. in our patients. "
Dr. Mamcarz stated that the current treatment, which is also being tested in older patients of SCID-XI whose bone marrow transplant was unsuccessful, was able to deliver to a patient of corrected gene cells, which was impossible before.
"We think this type of virus is safer and more effective," she said.
"It's the best we have so far for gene therapy."
& # 39; These children are cured & # 39;
It will be several years before researchers know for sure whether the treatment is effective in the long term.
But for now, the results suggest that children are cured, said Dr. Mamcarz.
"The majority of these patients have spent the first few months of their lives in the hospital, some of them suffering from serious infections in intensive care units and receiving multiple medications to keep them alive. "she said.
"They are now young children, exploring life and attending a daycare.
"This part has been extremely rewarding."
The researchers now hope that the treatment will provide a model for developing gene therapies for other blood and genetic disorders.
John Rasko, responsible for cellular and molecular therapies at the Royal Prince Alfred Hospital and who did not participate in the study, said that while long-term follow-up studies are needed, the results obtained to date are solid.
"We need studies on the safety and surveillance of these babies for decades to see what complications could possibly occur," said Professor Rasko.
"But that's the best result that has been observed for babies with SCID-X1."
Merlin Crossley, professor of molecular biology at the University of New South Wales, added that it had always been difficult to get a donor compatible for stem cell transplants and that gene therapy was a promising alternative.
"It is quite reasonable that this becomes a routine treatment," said Professor Crossley, who did not participate in the trial.
"It is a terrible disease and it is important to look after these young children, now they have all their life in front of them."
ABC
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