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Gene therapy reverses rare immune disorder

Children born with a rare genetic disorder called X-linked severe combined immunodeficiency (X-SCID) don’t have a functioning immune system. As a result, they can’t fight off infections. Without treatment, an infant with X-SCID will usually die within the first year or two of life.

The best option for treatment of newly diagnosed infants with X-SCID has been stem-cell transplantation from a genetically matched sibling. But less than a quarter of children with X-SCID have a matched donor available. For those without a matched donor, standard treatment has been a half-matched bone marrow transplant from a parent. But most infants receiving this type of transplant only have part of their immune system, called T lymphocytes, restored. These infants will need lifelong injections of protective antibodies. In addition, as they grow into young adulthood, they may have chronic medical problems that affect growth, nutrition, and quality of life.

To develop a better approach to fix the immune systems of children with X-SCID, researchers have used gene therapy to alter patients’ own blood stem cells. An engineered virus brings a healthy copy of the gene into the stem cells to replace the mutated gene that causes the disease.

Early results from trials of gene therapy for X-SCID resulted in life-saving correction of T lymphocytes. But similar to bone marrow transplant from a parent, the immune restoration was incomplete. In addition, in those first gene therapy studies, almost a third of the children developed leukemia. The approach accidentally stimulated cells to grow uncontrollably. In later studies, improved design of the engineered virus didn’t cause cancer, but also didn’t fully restore a healthy immune system.

In 2010, Dr. Harry Malech of NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and Dr. Brian Sorrentino of St. Jude Children’s Research Hospital reported a new and safer version of gene therapy for X-SCID. They designed a harmless engineered virus (called a lentivector) that could deliver genes into cells without activating other genes that can cause cancer. Before the altered stem cells were returned to their bodies, patients were given low doses of the chemotherapy drug busulfan. This made it easier for the new stem cells to grow in the bone marrow. In young adults and children treated at the NIH Clinical Center, the new therapy proved to be both safe and effective at restoring the full range of immune functions.

Based on this work, a team led by Dr. Ewelina Mamcarz of St. Jude Children’s Research Hospital began treatment in 2015 of newly diagnosed infants with X-SCID using the lentivector and busulfan. The work was funded in part by NHLBI. The team described the treatment of eight infants with the disorder on April 18, 2019, in the New England Journal of Medicine.

By 3 to 4 months after infusion of the repaired stem cells, 7 of the 8 infants had normal levels of multiple types of immune cells in their blood. The last infant required a second stem-cell infusion, after which his immune-cell levels rose to a normal range.

The infants’ new immune systems were able to fight off infections that the researchers had detected before the gene therapy. Four of the eight discontinued immune-system boosting medications that they’d previously needed. Of those four, three developed antibodies in response to vaccination, indicating a fully functional immune system.

A year and a half after gene therapy, all children were healthy and growing normally.

“The broad scope of immune function that our gene therapy approach has restored to infants with X-SCID — as well as to older children and young adults in our continuing study at NIH — is unprecedented,” Malech says.

The researchers will continue to follow the participants over time. They plan to track how the children’s immune systems develop and look for any late side effects.

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