Eight infants with the life-threatening inherited disorder X-linked severe combined immunodeficiency (SCID-X1), in which immune cells do not develop or function normally, have been cured through an experimental gene therapy. Although a small number of patients, the improvements in their immune system function and normal growth up to two years after treatment suggests that this new approach is safer and more effective than previously tested gene-therapy strategies for SCID-X1.

Interim results from the clinical trial were published this week in The New England Journal of Medicine in a paper titled “Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1.”

“These patients are toddlers now, who are responding to vaccinations and have immune systems to make all immune cells they need for protection from infections as they explore the world and live normal lives. This is a first for patients with SCID-X1,” said Ewelina Mamcarz, MD, a member of the St. Jude department of bone marrow transplantation and cellular therapy.

SCID is caused by a mutation in the interleukin-2 receptor subunit gamma (IL2RG) gene that produces a protein essential for normal immune function. The team performed a dual-center, Phase I–II safety and efficacy study of a lentiviral vector to transfer IL2RG cDNA to bone marrow stem cells in the infants with newly diagnosed SCID-X1. Prior to the gene-corrected blood stem cells being infused back into patients, the infants received two days of low-dose busulfan with the doses individually determined based on each patient’s specific ability to process the drug.

The infants were followed for roughly 16 months. In seven infants, the numbers of CD3+, CD4+, and naive CD4+ T cells and NK cells normalized by 3–4 months after infusion and were accompanied by vector marking in T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors. The eighth infant had an insufficient T-cell count initially, but T cells developed in this infant after a boost of gene-corrected cells. IgM levels normalized in seven of the eight infants, of whom four discontinued intravenous immune globulin supplementation; three of these four infants had a response to vaccines.

“While longer follow-up is needed to assess any late effects of treatment, these results suggest most patients treated with this gene therapy will develop a complete durable immune response without side effects,” Morton Cowan, MD, professor of pediatrics at the University of California, San Francisco and an author on the paper, said.

Infants with SCID-X1 are highly susceptible to severe infections. If untreated, the disease is fatal, usually within the first year or two of life. Currently, the best treatment for SCID-X1 is bone marrow transplantation with a tissue-matched sibling donor. However, less than 20% of infants with the disease have such a donor and must rely on blood stem cells from other donors. Those without a matched sibling typically receive transplants from a parent or other donor, which are lifesaving, but often only partially restore immunity.

“The broad scope of immune function that our gene therapy approach has restored to infants with X-SCID—as well as to older children and young adults in our study at NIH—is unprecedented,” said Harry Malech, MD, chief of the genetic immunotherapy section in NIAID’s Laboratory of Clinical Immunology and Microbiology and author on the paper.

Compared with previously tested gene-therapy strategies for SCID-X1, which used other vectors and chemotherapy regimens, the current approach appears safer and more effective. In these earlier studies, gene therapy restored T cell function but did not fully restore the function of other key immune cells, including B cells and NK cells. In the current study, not only did participants develop NK cells and B cells, but four infants were able to discontinue treatment with intravenous immunoglobulins which boost immunity. Three of the four developed antibody responses to childhood vaccinations—an indication of robust B-cell function.

Moreover, some participants in certain early gene therapy studies later developed leukemia, which scientists suspect was because the vector activated genes that control cell growth. The lentiviral vector used in the current study is designed to avoid this outcome.

The authors note that in addition to enrolling additional infants into the trial, “long-term follow-up will be required to assess the durability of the immune reconstitution and the persistence of the transferred gene in hematopoietic and immune cells and to monitor the patients for potential late effects of busulfan conditioning and gene therapy.”