Two months after being born, Eliana Nachem began to have a cough that would not go away. Three weeks later, she also started having diarrhea, so they took her to the pediatrician.
Nachem had no allergies or gastrointestinal problems; Instead, tests pointed to a problem with his immune system. At 4 months, Nachem received the diagnosis: severe combined immunodeficiency, or SCID.
Babies born with this extremely rare disease do not develop the cells necessary for the immune system to function. Each germ becomes a potentially deadly threat, and to stay healthy, children with this condition must live in a completely sterile environment. Without treatment, children usually do not live beyond 2 years.
“I prepared myself for the worst and I immediately started investigating,” said Jeff Nachem, Nachem’s father.
The Nachems also got to work turning their home into a germ-free fortress, relocating their pets, never opening the windows, and opening the doors to the outside as little as possible. Eliana Nachem stayed at home and, on the rare occasions when they had visitors, the family provided them with disposable gowns, gloves and masks to wear. (SCID is sometimes known as “bubble boy disease.”) The girl also began temporary therapy that replaced an enzyme that was missing in her body, called adenosine deaminase (ADA).
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Amid the strict protocol, they learned of a clinical trial in Los Angeles, 2,600 miles from their home in Fredericksburg, Virginia, that could help their daughter live a normal life.
Scientists have identified about 20 genetic variants that cause SCID. The form of the disease that Eliana Nachem suffers from, ADA-SCID, is diagnosed in fewer than 10 children born in the United States each year. (Fewer than 100 babies are diagnosed with some form of SCID in a year.)
In 2014, when she was just 10 months old, Machen was one of 62 children enrolled in a gene therapy clinical trial for ADA-SCID. In a study published this Wednesday in the journal New England Journal of Medicineresearchers followed up on the results of that Phase II clinical trial. The update reported that all 62 children who received the treatment between 2012 and 2019 are still alive today. In 59 of them, including Eliana Machen, the gene therapy completely restored immune function, without the need for any additional treatment, a success rate of 95%.
“This is one of the most successful gene therapy trials for an ultra-rare genetic disease that we have,” said Dr. Talal Mousallem, associate professor of Pediatrics at Duke University School of Medicine, who was not involved in the trial.
Stem cell correction
Treatment begins with the extraction of stem cells from the patient’s own bone marrow. These stem cells are purified in a laboratory and then modified using an inactive form of the virus that causes HIV. Instead of carrying the human immunodeficiency virus, this version carries the ADA gene that is missing in people with ADA-SCID, reinserting the gene into the DNA of stem cells.
Before the personalized treatment is introduced to the patient, he or she must undergo chemotherapy to eliminate existing stem cells in the body and make room for new ones. Once back in the body, the cells, which no longer carry the virus, but only the gene it left behind, go to work to build an immune system over the next year.
“It’s a single delivery vehicle that delivers the gene to the stem cell’s DNA, so every time it divides to create other cells, they carry the ADA gene,” explained Dr. Donald Kohn, a pediatric bone marrow transplant physician at UCLA’s Broad Stem Cell Research Center, who led the trial.
A less risky option
Gene therapy clinical trials are underway for four subtypes of SCID, but the standard treatment remains bone marrow transplant, which creates an immune system using stem cells from a donor. Treatment can be risky and have long-term side effects.
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Ideally, bone marrow transplants should be performed between siblings, who share about half of the same DNA, but there is only a 25% chance that two siblings will be compatible. In most cases, the donor is not a sibling, which carries the risk of the donor’s immune cells attacking the recipient’s body, a phenomenon called graft-versus-host disease.
The risk of graft versus host means that children who receive functional stem cells from another person must take immunosuppressive medications after the transplant, which prevent foreign cells from attacking their immune system.
“This slows down progress, because you’re suppressing the immune system at the same time you’re trying to build an immune system,” Kohn said.
People must also undergo much higher doses of chemotherapy before receiving a donor bone marrow transplant than they would before undergoing gene therapy.
“Chemotherapy treatment can have effects (later in life) on growth, the endocrine system or fertility,” explained Dr. Whitney Reid, an attending physician in the division of allergology and immunology at Children’s Hospital of Philadelphia, who was not involved in the trial.
With gene therapy, “those patients can be given much lower doses of chemotherapy and there is much less chance of rejection,” he said.
Having another therapy for ADA-SCID is especially important, Reid added. Changes in the ADA gene cause the buildup of toxins in groups of white blood cells called lymphocytes. This can cause hearing loss and learning difficulties as children grow.
Unlike other types of SCID, “it doesn’t just affect the immune system,” Reid added.
Duke University’s Mousallem said he hopes the success of this trial will open the door to gene therapies for other rare diseases that often go untreated, as well as for SCID caused by other genetic variants.
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“The data are excellent for ADA-SCID, and we hope that one day it will become the standard of care,” he said.
Eliana Machen turns 12 this week who comes and loves to go to dance classes.
“It’s amazing that she went from living in isolation to being able to go to preschool, swim in a public pool, play on a playground and do all the things other kids do,” her father said.
Machen continues to undergo testing twice a year to make sure his immune system hasn’t weakened. So far, everything is going well.
“We believe it is a therapy for life”Kohn commented. “Some of these kids are now 15 years old and leading normal lives. We treated them when they were babies and now they’re going to prom.”
