New results from the treatment of 50 children with so-called "bubble boy disease" show that the therapy succeeded in replacing the defective gene that causes the condition, erasing the condition in 48. The therapy produced engraftment of cells that corrected severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID) in 29 of 30 U.S. patients and 19 of 20 children in the U.K. To call it a cure "implies lifelong permanence. We don't know that," chief author Dr. Donald Kohn of the University of California, Los Angeles, told Reuters Health by phone. "The longest patient is six to seven years out. We hope it is lifelong." His key message: "Gene therapy works. We can talk about the two where it didn't work, but the glass is 96% full. Forty-eight of these kids are alive, healthy, not on antibiotics and we've restored their immune systems enough for them to have normal lives." The results were released at the virtual annual meeting of the American Society of Gene and Cell Therapy and published in the New England Journal of Medicine. Most children with (ADA-SCID) die within two years because their immune system can't fight off infections. The investigational gene therapy, known as OTL-101, uses autologous CD34+ hematopoietic stem and progenitor cells along with a self-inactivating lentiviral vector that contains the genetic code for the healthy gene to replace the defective version that leads to ADA deficiency. It has been given both Orphan Drug and Breakthrough Therapy designations by the U.S. Food and Drug Administration. Before the therapy, 49 of the 50 children, who were as old as 16, were receiving enzyme-replacement therapy and prophylactic antimicrobials. After 24 months of follow-up in the U.S. and 36 months in the U.K., two patients were withdrawn from the study because engraftment failed to be sustained. "One had the gene correct itself but the effect went away. And with one child in London, who got the lowest cell dose, the decision was made that it was too little to sustain lifelong protection," said Dr. Kohn. "Both had bone marrow transplants from other donors and have done okay." Twenty-three serious infections - of many different types - were seen in 15 patients. There were no deaths. One indication of the effectiveness of the treatment: 17 of the 18 children who received a tetanus vaccination during the study "had normal antibody responses when tested at least 3 months after cessation to immunoglobulin-replacement therapy," the researchers report. "Evidence of sustained immune reconstruction and thymic recovery was clear in most patients, and the large majority of patients were no longer receiving immunoglobulin-replacement therapy by the end of the study," the researchers said. "Severe infection rates were highest in the first 3 months after treatment, as expected because of conditioning, but were generally low across the full post-treatment period in all studies." Most of the side effects were considered related to conditioning for the treatment and were considered mild or moderate. In the U.S., 17% of the 421 adverse events were rated grade 3 or 4. Twelve of the 30 patients had one or more serious adverse events such as frequent infections or gastrointestinal problems. In the U.K., 19% of 321 adverse events were rated as moderate to severe. Eleven of the 20 patients had a serious event. There were no cases of graft-versus host disease or autoimmune problems. The surprise is "just really how consistently it works," said Dr. Kohn, a professor of microbiology, immunology and molecular genetics. "I've been in this field for about 35 years. We had many years wandering the wilderness where nothing worked," he said. "And because it's their own cells, we give much less chemotherapy and we don't give any immune suppression. We just give enough chemotherapy to make enough space for the new cells to engraft in the marrow. It's a relatively mild treatment." —Gene Emery Source
