Two months after Eliana was born, Nahem fell ill with a persistent cough. Three weeks later, she also began having loose stools, prompting her to see her pediatrician.
Eliana had no allergies or gastrointestinal problems; instead, tests pointed to a problem with her immune system. At 4 months Eliana was diagnosed with: severe combined immunodeficiency or SCID.
Babies born with the extremely rare disease do not develop the cells they need to function. immune system. Every germ becomes a potentially deadly threat, and children with this disease must live in a completely sterile environment to remain healthy. Without treatment, children usually do not live to see their second birthday.
“I expected the worst and then immediately went into research mode,” Eliana's father, Jeff Nachem, said.
The Nahems also went to work turning their home into a germ-proof fortress by rehoming their pets, never opening windows and opening doors to the outside as little as possible. Eliana was kept inside, and on the rare occasions when visitors came, the family had disposable gowns, gloves and masks for them. (SCID is sometimes called “bubble boy disease.”) Eliana also began temporary therapy to replace an enzyme that her body was missing called adenosine deaminase (ADA).
In the midst of 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 gene variants that cause SCID. A form of Eliana's disease, ADA-SCID, is diagnosed in fewer than 10 babies born in the United States each year. (Fewer than 100 babies are diagnosed with any form of SCID in a year.)
In 2014, when she was just 10 months old, Eliana was one of 62 children participating in a clinical trial gene therapy for ADA-SCID. In a study published Wednesday in the journal New England Journal of Medicineresearchers tracked the results of this Phase 2 clinical trial. The report states that all 62 children treated from 2012 to 2019 are alive today. In 59 of them, including Eliana, gene therapy completely restored immune function without requiring any additional treatment – a success rate of 95%.
“This is one of the most successful gene therapy trials we have for an ultra-rare genetic disease,” said Dr. Talal Musallem, assistant professor of pediatrics at Duke University School of Medicine. He did not participate in the trial.
Stem cell correction
Treatment starts with doctors obtaining stem cells from the patient's own bone marrow. These stem cells are purified in the laboratory and then modified with an inactivated form of the virus that causes HIV. Instead of the human immunodeficiency virus, this version contains the ADA gene, which people with ADA-SCID do not have, which reinserts the gene into the DNA of stem cells.
Before the customized treatment can be reinfused back into the patient, they must undergo chemotherapy to rid the body of existing substances. stem cells and make room for new ones. Once back in the body, the cells, which no longer carry the virus but only its remaining gene, begin to build an immune system over the next year.
“It's a one-time delivery vehicle that carries the gene into the DNA of the stem cell, so every time it divides to make other cells, those cells carry that ADA gene,” said Dr. Donald Cohn, a pediatric bone marrow transplant physician at the UCLA Broad Stem Cell Research Center, who led the study.
Less risky option
Clinical trials of gene therapy for the four subtypes of SCID are ongoing, but the standard of care remains bone marrow transplantation, which builds the immune system using stem cells from a donor. Treatment may be risky and have side effects.
Ideally, a bone marrow transplant occurs between siblings who share approximately half the same DNA, but the chance of two siblings being a match is only about 25%. In most cases, the donor is not a sibling, which creates a risk that the donor's immune cells will attack the recipient's body, a phenomenon called graft-versus-host disease.
The risk of graft-versus-host disease means that children who receive functioning stem cells from another person must take immunosuppressive drugs after the transplant, which prevent the foreign cells from attacking their immune system.
“It slows down progress because you're suppressing the immune system while trying to build up the immune system,” Cohn said.
People also have to undergo much higher doses of chemotherapy before a bone marrow transplant than before undergoing gene therapy.
“There may be consequences [later in life] from chemotherapy treatment, including effects on growth, the endocrine system or fertility,” said Dr. Whitney Reed, an attending physician in the department of allergy and immunology at Children's Hospital of Philadelphia, who was not involved in the study.
With gene therapy, “you can give these patients much lower doses of chemotherapy, and the likelihood of rejection will be much lower,” she said.
The availability of other treatments for ADA-SCID is especially important, Reed added. Changes in the ADA gene cause toxins to accumulate in clusters of white blood cells called lymphocytes. This can lead to hearing loss and learning difficulties as children grow older.
Unlike other types of SCID, “it affects more than just the immune system,” Reed said.
Duke University's Musallem said he hopes the success of this study will open the door to gene therapy for other rare diseases that often go untreated, as well as SCID caused by other gene variants.
“The data on ADA-SCID is excellent, and we hope that one day it will become the standard of care,” he said.
Eliana turns 12 next week and loves going to dance lessons.
“It's amazing that she was able to go from living in isolation to being able to go to daycare, swim in the public pool, play on the playground and do all the things that any other child can do,” her father said.
Eliana still gets tested twice a year to make sure her immune system isn't weakened. So far, so good.
“We think this is a lifelong therapy,” Cohn said. “Some of these kids are now 15 years old and living normal lives. We treated them when they were little, and now they're going to prom.”
