According to a December 22 study in the New England Journal of Medicine.
The children have Artemis-SCID, a very rare genetic disease that is usually treated with a bone marrow transplant from a healthy donor, ideally a compatible sibling. The new gene therapy allows researchers to treat newly diagnosed babies with their own cells — adding a healthy copy of the Artemis gene to marrow stem cells harvested from the baby, then infusing the corrected stem cells into their bodies — in hopes avoid many of the short- and long-term complications of standard treatment, including death.
The children in the trial — all under the age of 5 — live at home with their families, attend daycare and preschool, play outside and lead normal lives, said Mort Cowan, MD, professor of pediatrics. at UCSF and principal investigator of the trial. .
“Already, their disease progression is so much better than with typical treatment,” said Cowan, who has treated more than 30 children with Artemis-SCID using standard bone marrow transplants. “I have never seen such results in any of the other children. It’s incredible. »
Genetic correction has previously been used in patients with other genetic forms of SCID, but its use in Artemis-SCID is important because these patients generally respond less well to standard bone marrow transplants. Complications can include bone marrow transplant rejection, graft versus host disease – in which donor T cells attack recipient tissue – chronic infections leading to organ damage, growth retardation and premature death .
Signs of stronger immunity
The first result of the phase I/II trial involved the safe transfusion of genetically corrected cells that would differentiate into white blood cells 42 days following infusion. The researchers hypothesized that patients would need less chemotherapy to prepare their marrow for transfusion when their own cells were used; thus only 25% of a full dose of busulfan was administered. The second outcome was T cell reconstitution at 12 months, a measure of the strength of the immune system.
All 10 patients were safely transfused with their own genetically corrected stem cells which gave rise to corrected peripheral blood cells within 42 days. All 10 were developing their own T-cells and B-cells at 12 weeks, and four of nine (excluding one patient who received a second treatment) achieved full T-cell immune reconstitution at 12 months. Four out of nine also achieved full B-cell immunity at 24 months, allowing them to stop immunoglobulin replacement and receive standard childhood vaccinations. Three other patients, who were followed for less than 24 months, showed promising B cell development compared to previous results for donor transplant patients.
One child required a second gene-corrected bone marrow infusion due to persistent cytomegalovirus infection prior to gene therapy, but is now infection-free with good T- and B-cell immunity.” All results are better than those previously seen with Artemis-SCID patients who received donor bone marrow transplants,” noted Jennifer Puck, MD, professor of pediatrics at UCSF and co-principal investigator of the study. .
“The fact that the patients in the trial achieve complete immunity once morest T cells is exceptional. B-cell recovery takes longer, but so far it seems patients also have a much better chance of B-cell recovery than they would with 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 might help stave off problems like chronic lung disease that often develops later in childhood for Artemis-SCID patients who receive standard bone marrow transplantation, Cowan added.
Children in the trial currently range in age from 18 months to 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 with clinical illness at five months of age. Four patients are of Navajo/Apache Indian descent, where the Artemis-SCID mutation is more common. The median follow-up was 31.2 months. At the time of publication of the study, six patients had been followed for at least 24 months.
“We are currently pioneering gene therapy in this very rare disease, but we are using techniques that can be exported to other situations and can help many other conditions around the world,” Puck said. “Each new innovation comes one patient at a time. »
Co-Authors: Also contributing to this UCSF research: Jason Yu, PhD; Carol Fraser-Browne, BA; Ukina Sanford, MS; Misako Kawahara, BA; Wendy Chan, BS; Shivali Chag, MS; and Robert Currier, PhD, of the UCSF Department of Pediatrics; Jess Oh, MS, of UCSF Benioff Children’s Hospital in San Francisco; Jasmine Dara, MD; Janelle Facchino, NP; Christopher Dvorak, MD, of the UCSF Department of Pediatrics and UCSF Benioff Children’s Hospital in San Francisco; Joan Hilton, DSc, MPH, of the UCSF Department of Epidemiology and Biostatistics; and Janel Long-Boyle, PharmD, PhD, of the UCSF Department of Pediatrics, School of Pharmacy, and Benioff Children’s Hospital at UCSF San Francisco. Please refer to the article for additional co-authors.