Eliana was just three months old when she was diagnosed with ADA-SCID, a rare immune disorder that can be deadly if left untreated. Now 11 years old, she is one of five children born with this genetic condition who have been healthy for more than a decade, thanks to a gene therapy developed by UCLA and University College London.
Published today in the journal Blood, long-term follow-up data from 62 children treated with this gene therapy between 2012 and 2019 show a 95% success rate, with no serious complications reported. Armed with this clinical data from the largest and longest study for a gene therapy of its kind, the researchers are aiming for the treatment to receive FDA approval within the next two to three years.
“These results are what we hoped for when we first began developing this approach,” said Donald B. Kohn, MD, professor of microbiology, immunology and molecular genetics at UCLA. “The durability of immune function, the consistency over time and the continued safety profile are all incredibly encouraging.”
ADA-SCID is caused by mutations in the gene that encodes for the adenosine deaminase (ADA) enzyme, resulting in the accumulation of toxic compounds that prevent white blood cells from maturing normally and fighting off infections. Without treatment, the life expectancy for children born with this condition is lower than two years.
Children diagnosed with ADA-SCID typically receive enzyme and immunoglobulin replacement therapy, which can help partially restore their immune function, followed by a bone marrow transplant to replace their immune cells with those from a healthy donor. While this approach has significantly increased survival rates, life-long immunosuppressive therapy is required to prevent the transplanted immune cells from attacking the body, often causing long-term complications.
In contrast, the gene therapy developed by Kohn and colleagues could leave children healthy and treatment-free after a single infusion. As part of the treatment, blood stem cells collected from the patient are modified, using a lentivirus to deliver a healthy copy of the faulty ADA gene, and then infused back into the patient. These engineered stem cells immediately start producing healthy immune cells, and it takes between six to 12 months for the immune system to fully restore to normal levels.
In 59 out of 62 children treated, the engineered cells successfully engrafted after six months. They have all remained off enzyme replacement therapy, naturally producing normal levels of the ADA enzyme. All but one of these patients were also able to discontinue immunoglobulin replacement therapy, developing healthy immune responses of their own in response to vaccinations.
“Treatment was successful in all but three of the 62 cases, and all of those children were able to return to current standard-of-care therapies,” said Kohn. “What’s most remarkable is that everything has been completely stable beyond the initial three-to-six-month recovery period.”
No serious side effects were reported during the trial, other than those associated with the chemotherapy course required to prepare the patients for the gene therapy infusion. The children have so far been followed up for a minimum of five years, with five of them reported to remain disease-free for over a decade.
Soon, this treatment could be widely available to children born with ADA-SCID. “Our goal is to have this therapy FDA-approved within two to three years,” said Kohn. “The clinical data strongly supports approval—now we need to demonstrate that we can manufacture the treatment under commercial pharmaceutical standards.”
As part of the trial, the researchers have also been testing the possibility of freezing the blood stem cells during the manufacturing process to gain more time for testing and quality control before treatment. More than half of the patients received a frozen preparation of the gene therapy, showing similar outcomes to those who received cells that were not frozen.
“The freezing approach allows children with ADA-SCID to have their stem cells collected locally, then processed at a manufacturing facility elsewhere and shipped back to a hospital near them,” said Katelyn Masiuk, MD, PhD, former clinical project lead at UCLA and now chief scientific officer of Rarity PBC, a public benefit corporation bringing this and other gene therapies to market. “This removes the need for patients and their families to travel long distances to specialist centers.”
If the gene therapy receives regulatory approval, many more children like Eliana could be given another chance at leading normal lives. Her mother reports that despite some early complications during the recovery period, Eliana has been able to leave behind the strict medical isolation and sterilization of all her food and toys, and is now able to do things like attend public school and play basketball.
