First Demonstration of “Apparently Fully Curative” Gene Therapy
Medscape Medical News
by: Zosia Chustecka
December 11, 2006 (Orlando) — Success with gene therapy in infants with severe combined immunodeficiency (SCID) reported at the American Society of Hematology (ASH) 48th Annual Meeting and Exposition spells “good news for the whole field of gene therapy,” say the researchers.
The results come from a trial of 8 children (aged 7 months to 5.5 years) with SCID caused by a defective gene for adenosine deaminase (ADA). These infants are so immunocompromised that any infection is potentially life threatening, and they often spend their short lives encased in a plastic “bubble.” They were treated with transduced autologous hematopoietic stem cells transfected with the ADA gene, inserted via retroviral-mediated transfer.
“All of the children are currently healthy and thriving,” lead researcher Alessandro Aiuti, MD, from the San Raffaele Telethon Institute for Gene Therapy, in Milan, Italy, told the meeting. “They are living normal lives and are going to school and kindergarten.” They have shown no adverse events related to the gene transfer, and none have developed severe infections.
All of the infants with longer follow-up who have a completely reconstituted immune system do not require any treatment, so it appears that the gene therapy is “curative,” Dr. Aiuti told Medscape. However, this reconstitution takes time, and before the process is completed, patients are given immunoglobulins, he added. Before entry into the trial, 6 of 8 children were on ADA enzyme-replacement therapy.
“This is the first demonstration of an apparently fully curative gene-therapy transplant,” Stephen Emerson, MD, PhD, from the University of Pennsylvania, in Philadelphia, told Medscape. These children have gone from “bubble to playground,” he said.
Speaking as the moderator of an ASH press conference at which this trial was highlighted, Dr. Emerson said the results are good news for the whole field of gene therapy. “In this trial, the gene therapy offered tremendous benefits with no toxicity, and it offers real promise for the future for the potential of gene therapy in more common and more complex diseases, such as sickle-cell anemia and thalassemia.”
Also speaking at the press conference, Dr Aiuti explained that previous attempts at gene therapy for ADA-SCID have not been totally successful, as the children continued to need enzyme-replacement therapy (with pegylated ADA). One of the innovations in their own protocol was the use of the cytoxic agent busulfan, which helps the engraftment process by “making room for the new stem cells,” he commented. Busulfan was administered at 2 mg/kg per day on days 3 and 2 prior to the transplant and resulted in a transient myelosuppression in most patients, although in 2 patients this myelosuppression was prolonged. “It appears that the greater the extent of neutropenia, the better the engraftment,” Dr Aiuti commented.
It appears that the gene therapy results in persistent gene correction, Dr. Aiuti commented. Long-term engraftment of the transduced cells was demonstrated by stable multilineage marking: T-cell counts were normal, and there was a restoration of T-cell function. There were also metabolic benefits — the children did not need treatment with pegylated ADA enzyme replacement, and 7 of 8 patients showed an increase in both height and weight. “The 1 patient who didn’t was treated at an older age, so there was probably more damage there,” Dr. Aiuti said.
The median follow-up is 3 years, and the longest is 6 years, but there is real hope that the effects will “last for a lifetime,” he said.
Dr. Aiuti and colleagues are continuing with this approach and have so far treated 1 other patient. They concluded that the data so far “confirm the safety and the efficacy of gene therapy in improving immune and metabolic function in children diagnosed with ADA-SCID” and suggested that this approach “may represent a viable solution to reduce the mortality rates associated with SCID in newborns.”
ASH 48th Annual Meeting and Exposition: Abstract 200. Presented December 11, 2006.
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