A new gene therapy has been shown to be safe and effective in 10 young children who were recently diagnosed with a rare immunodeficiency disorder. This disorder, Artemis-deficient severe combined immunodeficiency (ART-SCID), is typically treated by means of allogeneic hematopoietic-cell transplantation—that is, with a bone marrow transplant from a healthy donor, ideally a matched brother or sister. Because ART-SCID is poorly responsive to conventional treatment, scientists based at UC San Francisco (UCSF) pioneered a new therapeutic approach, one that introduces a functional gene for the Artemis protein, an endonuclease that helps repair double-strand DNA breaks and plays a crucial role in the development of B and T lymphocytes.

The new approach was evaluated in a Phase I/II trial in which stem cells were harvested from the patients and subjected to transduction by means of a self-inactivating lentiviral vector. This vector incorporated a functional copy of the DCLRE1C gene, that is, the gene that encodes the Artemis protein. Then, the modified cells were reintroduced to the patients.

Results from the trial appeared recently in the New England Journal of Medicine, in an article titled, “Lentiviral Gene Therapy for Artemis-Deficient SCID.”

“Infusion of lentiviral gene-corrected autologous CD34+ cells, preceded by pharmacologically targeted low-exposure busulfan, in infants with newly diagnosed ART-SCID, resulted in genetically corrected and functional T and B cells,” the article’s authors wrote. “We found that this approach restored immunity and was safe (within the context of the disease and alternative approaches) and conclude that further studies are warranted.”

The children in the trial—all under the age of 5—are living at home with their families, attending daycare and preschool, playing outside, and living normal lives, said Mort Cowan, MD, UCSF pediatrics professor and the trial’s lead investigator.

“Already, the course of their illness is so much better than with the typical treatment,” said Cowan, who has treated more than 30 children with ART-SCID using standard bone marrow transplants. “I’ve never seen results like this in any of the other kids. It’s amazing.”

Gene correction has been used before in patients with other genetic forms of SCID, but its use in ART-SCID is significant because these patients usually respond more poorly to standard bone marrow transplants. Complications can include rejecting the marrow graft, graft-vs.-host disease, chronic infections leading to organ damage, stunted growth, and premature death.

When the trial began in 2018, the first enrollee, “HT,” was still an infant. His grandmother and caretaker, Laverna Shorty, has seen HT go through a lot of pain in his first years. HT’s condition was discovered shortly after his birth in Arizona, and he was airlifted to UCSF for treatment.

“HT was born with ART-SCID, but after he went through the trial, he’s living a normal life now,” Shorty said. “He’s not sick anymore. He discarded all of his medication. He’s happy and he’s growing to be a young man.”

The first outcome of the Phase I/II trial involved the safe transfusion of gene-corrected cells that would differentiate into white blood cells by 42 days after infusion. Researchers theorized patients would need less chemotherapy to prepare their marrow for transfusion when their own cells were being used; thus only 25% of a full dose of busulfan was administered. The second outcome was T-cell reconstitution at 12 months, a measurement of the strength of the immune system.

All 10 patients were safely transfused with their own gene-corrected stem cells that gave rise to corrected peripheral blood cells within 42 days. All 10 were growing their own T cells and B cells by 12 weeks, and four of nine (excluding a patient who received a second treatment) achieved full T-cell immune reconstitution by 12 months. Four of nine also achieved full B cell immunity by 24 months, allowing them to discontinue immunoglobulin replacement and receive standard childhood vaccinations. An additional three patients, who were followed for fewer than 24 months, had promising B cell development when compared to previous outcomes for donor-transplanted patients.

One child required a second infusion of gene-corrected bone marrow due to a persistent infection with cytomegalovirus prior to gene therapy but is now infection free with good T- and B-cell immunity. “All of the results are better than those previously seen with Artemis-SCID patients who received donor bone marrow transplants,” noted Jennifer Puck, MD, UCSF pediatrics professor and co-lead investigator in the study.

“Having patients in the trial achieve full T-cell immunity is outstanding. B-cell recovery takes longer, but so far it looks as if the patients also have a far better chance for B-cell reconstitution than they would with a regular bone marrow transplant,” Puck said. “Successfully using less chemotherapy is also a big win, minimizing the harmful side effects of full dose busulfan in small infants.”

Better B-cell immunity could help avoid issues such as chronic lung disease that often develop later in childhood for ART-SCID patients who receive a standard bone marrow transplant, Cowan added.

The children in the trial are currently between the ages of 18 months and 4.5 years; nine were born in the United States and were diagnosed following newborn screening for SCID; one was born in Canada and diagnosed at five months of age with clinical illness. Four patients are of Navajo/Apache Native American descent, where the ART-SCID mutation is more common. Median follow-up was 31.2 months. At the time of study publication, six patients had been followed for at least 24 months.

“We’re pioneering gene therapy in this very rare disease right now, but we are using techniques that can be exported to other situations and can help many other conditions worldwide,” Puck declared. “Every new innovation happens one patient at a time.”

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