Precision Medicine Therapy Restores Immune Function in Children

A precision medicine therapy developed by researchers at UCLA and Great Ormond Street Hospital (GOSH) in London restored immune function in more than 95 percent of pediatric patients.

Using the experimental approach, the team successfully treated 48 of 50 children born with a deadly and inherited disorder that keeps them from having a functioning immune system.

Severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID) is caused by mutations in the ADA gene that creates the enzyme adenosine deaminase. This enzyme is essential for a functioning immune system.

Children with the condition can develop serious, life-threatening infections from doing day-to-day activities, like going to school or seeing friends. If left untreated, the condition can be fatal within the first two years of life.

The precision medicine approach involves collecting some of the child’s blood-forming stem cells, which have the potential to create all kinds of blood and immune cells. Next, a new copy of the ADA gene is delivered into the stem cells by a modified viral vector. The corrected cells are then returned to the child’s body, where they are supposed to produce a continual supply of healthy immune cells capable of fighting infection.

Researchers from UCLA and GOSH reported two- and three-year outcomes for children treated with the gene therapy in clinical trials at GOSH, UCLA Mattel Children’s Hospital, and NIH between 2012 and 2017.

"Between all three clinical trials, 50 patients were treated, and the overall results were very encouraging," said Donald Kohn, a distinguished professor of microbiology, immunology, and molecular genetics and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

"All the patients are alive and well, and in more than 95 percent of them, the therapy appears to have corrected their underlying immune system problems."

There were no complications or treatment-limiting events reported among the patients, and most adverse events were mild to moderate. The team considered adverse events to be related to routine procedures performed in preparation for the experimental gene therapy treatment or effects of the immune system rebuilding.

"Treatment was successful in all but two of the 50 cases, and both of those children were able to return to current standard-of care-therapies and treatments, with one eventually receiving a bone marrow transplant," said Kohn.

The investigational precision medicine therapy is a one-time procedure that researchers believe could lead to lifelong results. The approach offers a potential new treatment option for children with ADA-SCID, who otherwise have to undergo once- or twice-weekly injections of the ADA enzyme until providers can find a matched bone marrow donor.

If physicians can’t find a matched bone marrow donor, patients require lifelong injections, in addition to antibiotics, antifungal medications, and monthly infusions of immunoglobin, which contains infection-fighting antibodies. Because these treatments are expensive, they are out of reach for many families.

"If approved in the future, this treatment could be standard for ADA-SCID, and potentially many other genetic conditions, removing the need to find a matched donor for a bone marrow transplant and the toxic side effects often associated with that treatment," said Claire Booth, a GOSH consultant in pediatric immunology and gene therapy.

Beginning in 2008, the research team developed an improved viral vector using a kind of virus called a lentivirus. Viruses of this kind can enter non-dividing cells’ nuclei, and when used as vectors, have the potential to make gene therapies safer and more effective.

ADA-SCID patients began receiving the new gene therapy at GOSH in 2012. In 2013, UCLA and NIH offered the experimental treatment.

"More than 200 patients with various genetic conditions across the world have now been treated with experimental lentiviral gene therapies, and applying gene therapy to ADA-SCID is another significant scientific advance," said Adrian Thrasher, a senior author of the study who is also a professor of pediatric immunology at GOSH.