ADA-SCID gene therapy trials to resume in 2023

Parents of children with adenosine deaminase (ADA) deficient severe combined immunodeficiency (SCID) learned that after several years of delay, clinical trials to treat ADA-SCID using gene therapy will resume in 2023.

Dr. Donald Kohn, University of California Los Angeles (UCLA) Department of Microbiology, Immunology, and Molecular Genetics distinguished professor and lead investigator on the trials, shared the news at an Immune Deficiency Foundation (IDF) SCID Compass Lunch & Learn in September.

The gene therapy clinical trials stalled in 2018, two years after Orchard Therapeutics licensed the treatment from UCLA with the intention of making it commercially available. Orchard failed to make progress in gaining Food and Drug Administration (FDA) approval for the treatment and for financial reasons decided not to make the investment necessary to continue with its development.

In May 2021, under pressure from parents whose children with ADA-SCID need gene therapy treatment, Orchard transferred the license back to UCLA. UCLA immediately resumed work on the trials but hit a roadblock in the spring of 2022 when the FDA requested amendments to the newly developed UCLA clinical protocol and manufacturing plans before allowing the clinical trials to move forward.

The extra work required by UCLA to meet the FDA demands took about six months and in September 2022 researchers re-submitted the modified protocol and plans. The FDA has 30 days to review it, and Kohn said if all goes well, enrollment in the trial can begin in January 2023, and his team can treat three to six patients within a year.

UCLA intends to move forward on the list of 26 children who have been waiting for treatment by providing treatment to those who’ve been on the list the longest. Three joined the list in 2017, five in 2018, four in 2019, four in 2020, seven in 2021, and three in 2022.

ADA deficiency is the cause of 10 to 15 percent of SCID cases, and about 10 babies are born each year with ADA-SCID across the U.S. and Canada.

Children with ADA-SCID lack an important enzyme called adenosine deaminase (ADA) which helps the body break down a chemical called deoxyadenosine that is toxic to white blood cells. Because the child doesn’t have the enzyme, the toxin builds up, kills white blood cells, including T cells, and causes SCID.

A temporary treatment option is enzyme replacement therapy (ERT). This therapy provides functional ADA enzyme, reducing the build-up of deoxyadenosine and allowing the child to make T cells. ERT is administered through one to two injections per week and is used until a more definitive treatment like bone marrow transplant (BMT) or gene therapy can be given.

Since not all children can find donor cells that closely match their own for BMT and BMT sometimes fails, gene therapy is an important alternative treatment. In gene therapy, doctors withdraw some of a child’s own stem cells, insert a working copy of the ADA gene into the cells, and infuse those cells back into the child where they produce a functioning immune system.

In clinical trials performed by UCLA and Great Ormond Street Hospital in the United Kingdom, from 2013 to 2018, 48 out of 50 children with ADA-SCID who underwent gene therapy developed a functioning immune system. All the children survived, but one didn’t engraft and later received a successful BMT, and another failed to reach sufficient engraftment and returned to ERT.

In the absence of support from Orchard, the California Institute for Regenerative Medicine (CIRM) is funding the clinical trials at UCLA, but eventually, researchers will have to partner with a company to produce the treatment commercially.

Barriers to treating all children on the waiting list include limits on funds, staff time, and vector (vector is a deactivated virus that delivers the corrected gene into a cell during gene therapy). Not enough funds from the current grant exist to treat 26 children and though there is enough vector to treat that number, said Kohn, the vector could lose its potency because it’s a biological material. A new batch of vector costs about $500,000 and takes about a year to obtain.

“Once we are up and going and we see we can treat more patients, we’ll put in another grant to CIRM to get more data to support the FDA application, and in that budget, we would request money to get another batch of vector and ideally would have that before we finish the current one,” said Kohn.

Kohn said after his team successfully treats three to six patients, they’ll move as far as they can with the others, but he cannot guarantee that all children on the list will receive treatment.

“We’ll try and treat as many patients as we can under the compassionate protocol with the limitations I mentioned. I don’t know if we’ll get through 26 patients. That may take two, three, or four years and more vector and more funding but we’ll try,” he said.