ABOVE: Newborn screening is now used in the US to detect severe combined immunodeficiency before infections set in.

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Treating infants with X-linked severe combined immunodeficiency with low-dose chemotherapy followed by gene therapy gave the children the ability to make the cells needed to mount a normal immune response, researchers report today (April 17) in the New England Journal of Medicine. The finding marks a milestone in the long effort to use gene therapy for the devastating condition, also known as bubble boy disease, which requires untreated patients to be isolated in order to protect them from life-threatening infections. Experts caution that longer follow-up is needed to determine whether the gene therapy–treated patients are truly cured.

“We were able to remove the protective isolation within three to four months post gene therapy and send the babies home to their families,” said Ewelina Mamcarz, a pediatric hematologist-oncologist at St. Jude’s Children’s Research Hospital in Tennessee, in a telephone press conference about the study. “They are all toddlers now, exploring life, attending daycares, and this part has been extremely rewarding.”

People with severe combined immunodeficiency (SCID) have mutations in genes needed for immune cell function, leaving them vulnerable to infection. In the most common form of the disease, X-linked SCID (SCID-X1), the gene at fault is IL2RG, which codes for a piece of the cytokine receptors needed for the normal development of several different kinds of immune cells, including T cells, B cells, and natural killer cells.

The standard treatment for the condition is a transplant of bone marrow tissue that can make normal immune cells, but finding an immunological match for patients can be a challenge. “For people who have a sibling match . . . by far that’s the best case scenario” for current treatment options, says Hey Chong, who heads the Division of Pediatric Allergy and Immunology at Children’s Hospital Pittsburgh and was not involved in the study. However, only about 20 percent of SCID-X1 patients have a matched sibling, and receiving a transplant from another donor carries a risk of graft-versus-host disease.

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Efforts to treat SCID-X1 with gene therapy began two decades ago. While they initially produced promising results, the earliest therapies appeared to cause leukemia in some patients. Mamcarz says that even later, safer iterations of gene therapy only restored T cells, not B cells, so patients needed to be treated with immune-boosting immunoglobulins after gene therapy in order to compensate for the missing cells and stay healthy.

The gene therapy in the new study, developed at St. Jude, delivers a functioning copy of IL2RG into patients’ extracted bone marrow cells using a lentiviral vector modeled on HIV’s shell. The IL2RG sequence comes with an insulator sequence at the end designed to prevent it from turning on nearby genes in the area of the genome it lands in, given that switching on the wrong gene could lead to cancer.

In addition to using a different vector from previous gene therapies, the study protocol called for a novel step, devised by researchers at the University of California, San Francisco (UCSF): pretreatment of patients with a low dose of the chemotherapy drug busulfan, which kills off immune precursors. Its aim was to create space around the bone marrow for the gene-edited cells to get in and take hold.

Ten infants were treated in the study, half at UCSF and half at St. Jude’s (the study reports results for the first eight). They ranged in age from 2–14 months at the time of treatment, and none had a matched sibling donor available. Doctors extracted bone marrow cells from each patient and sent them to a lab at St. Jude’s for editing. They then treated the babies with one to two doses of busulfan, and injected the gene-edited cells back into them.

The researchers monitored levels of the patients’ immune cells for a median of 16 months; all but one of the first eight saw climbing levels of T cells, B cells, and natural killer cells following the treatment. (The nonresponsive patient was re-treated with the gene therapy, which increased his T cell count.) Four of the patients received vaccinations against tetanus, diphtheria, pertussis, polio, and pneumonia, although only two of those infants mounted a normal immune response to all of the vaccines, as measured by counts of cells and other markers in their blood.

Gene therapy is going to be the way to go, certainly, for SCID diseases. —Andrew Gennery, Newcastle University

The fact that immune cell counts climbed to the point where researchers could give some of the patients vaccines “is really amazing,” says Charles Venditti, a pediatric geneticist at the National Human Genome Research Institute who was not involved in the study. While he considers the overall results impressive, he’d like to see a longer follow up, he says, noting that the response to the immunizations was variable. “In my mind, that doesn’t indicate that the B cell [phenotype has] been completely cured yet. It could take more time.”

Andrew Gennery, a pediatric immunologist at Newcastle University in the UK who was not involved in the study but has collaborated with some of its authors in the past, says he finds the results “very encouraging,” noting that the study is an early one with a small number of patients. Like Venditti, he’d also like to see data on how those patients who didn’t yet have normal B cells fare over a longer period of time. Ultimately, he says, “gene therapy is going to be the way to go, certainly, for SCID diseases. To my mind, at the moment, the biggest issue actually is going to be cost.”

St. Jude’s has licensed the SCID-X1 gene therapy to Mustang Bio and is working with the company to commercialize it. Mamcarz says “it’s too early to estimate the overall cost, but we want it to be accessible to any and every child who needs it.” She argues that the gene therapy will be more cost-effective than current treatment options, because at least some of the patients treated eventually are able to stay healthy without the need for immunoglobulins or other ongoing therapies.

A gene therapy treatment option would be especially beneficial for many nonwhite, and, in particular, mixed-race patients, who have less likelihood than whites of finding a well-matched donor in existing databases, says Chong. While she, too, would like to see a longer follow-up, “overall I think it’s really positive. . . . It’s going to be obviously fantastic for patients who don’t have a good match.”