Gene Therapy for SCID-X1 Safer in Second Iteration

Ricki Lewis, PhD

October 09, 2014

A second-generation gene therapy for X-linked severe combined immunodeficiency (SCID-X1) repeats the efficacy demonstrated in a previous clinical trial, but without the adverse event of leukemia that affected a quarter of the participants in the earlier study, according to a report published in the October 9 issue of the New England Journal of Medicine.

SCID-X1 is called "bubble boy disease" after a 13-year-old boy who died in 1984 after leaving an isolation apparatus to undergo a bone marrow transplant. The immunodeficiency impairs the interleukin 2 receptor gamma chain (IL2RG), which leads to the absence of T cells and natural killer cells, which in turn affects B cells. Most affected boys die of viral infection before their first birthdays.

Retooling the Viral Vector

For boys without a matched hematopoietic stem cell (HSC) donor, researchers have been trying to treat the disease through gene therapy, using a gamma retroviral vector that contains the missing IL2RG DNA sequence. However, in the initial clinical trial, which began in 1999, 5 of 20 patients developed T-cell acute lymphoblastic leukemia after the vector inserted into and activated an oncogene, LMO2 ( Science. 2003;302:415-419). The leukemia took 2 to 5.5 years to manifest. One child died.

Because the gene therapy was effective (18 of the 20 boys have functional immunity), an international team was formed to replace the control sequence in the vector that caused the leukemia and to try again. This time, so far, the gene therapy appears to be both effective and safe, S. Hacein-Bey-Abina, PharmD, PhD, from the Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris, Institut National de la Santé et de la Recherche Médicale, Paris, France, and colleagues report.

"The earlier vectors had strong enhancer elements that could activate genes near their insertion sites, which led to clonal outgrowth and progression to leukemia," coauthor Donald B. Kohn, MD, from the Department of Pediatrics, Children’s Discovery and Innovation Institute, University of California, Los Angeles; Mattel Children’s Hospital; and the Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, Los Angeles, told Medscape Medical News. The new "self-inactivating" vector uses a promoter sequence to a human gene (elongation factor alpha), "which is sufficiently strong to make enough of the relevant gene product, but lacks enhancers that can turn on adjacent genes," he added.

Second Trial

The current trial had two primary endpoints: to treat the genetic disease and to not cause leukemia. The authors report that seven of nine boys treated with the new vector have functional peripheral blood T cells a median of 33 months (range, 16 - 43 months) after treatment, and none has developed leukemia.

Boys enrolled in the study lacked an allogeneic donor or had an active, treatment-resistant infection. Functional IL2RG genes were introduced into CD34+ cells purified from each patient's bone marrow, and the cells were then reinfused into the patient.

After a single round of treatment, six boys had a T-cell count above 300 cells/μL of blood and T-cell proliferation in response to stimulation with phytohemagglutinin. A seventh boy who had low T-cell counts received a second round of gene therapy. His count is still low, but he is healthy. Gene therapy did not stimulate T-cell production in an eighth patient, but he is doing well after a conventional allogeneic HSC transplant. The remaining patient died of an adenovirus infection present at the time the trial began.

In addition to checking for leukemic cells, the investigators identified sites of vector integration in the boys' genomes and compared them with the integration profile in the earlier trial. Although second-generation viruses homed to transcriptionally active genes, as retroviruses do, they differed from the first-generation viruses at 21 sites, associating much less with cancer-associated genes (P < .001).

So successful is the gene therapy for SCID-X1 so far, and given the risk for graft rejection and graft-versus-host-disease in allogeneic HSC transplants, gene therapy "should become the standard of care," says James Wilson, MD, PhD, director of the Gene Therapy Program at the University of Pennsylvania.

Wider Applications

A third-generation approach for gene therapy for SCID-X1 uses a very different vector: lentivirus. Researchers at the Genetic Immunotherapy Section of the National Institute of Allergy and Infectious Diseases reported preliminary data, using lentivirus, on two patients with SCID-X1 who were in their 20s and who had received transplants as infants, at the American Society of Gene and Cell Therapy annual meeting last May. Both patients have improved and have not developed leukemia. "The best approach may be a lentiviral vector with a [self-inactivating] genome," says Dr Wilson, according to in vitro and mouse studies.

Dr Kohn broadens the significance of the success reported in the journal article. "For each genetic blood cell disease that can be treated with HSC transplants from a healthy donor, gene therapy which enables an autologous transplant could provide a safer approach." As likely disease candidates, he lists other forms of SCID, Wiskott-Aldrich syndrome, chronic granulomatous disease, beta-thalassemia, and adrenoleukodystrophy.

A limitation of the study is the latency of 2 to 5.5 years for the leukemia. Participants will be monitored for development of leukemia for 15 years.

Various authors report receiving financial support from the European Union; the German Research Foundation; the German Ministry of Research; the US Food and Drug Administration; European Union FP7; the European Research Council; the Health Ministry, Assistance Publique-Hôpitaux de Paris; the Medical Research Council; the National Institutes of Health; the National Institute of Allergy and Infectious Diseases; and Bluebird Bio. One coauthor also reports patents related to expression vectors having a reduced content of viral genes and retroviral vectors for gene transfer, both of which are licensed to Acpeth GmbH. Another coauthor reports pending patents related to the optimization of determinants for successful genetic correction of diseases, mediated by hematopoietic stem cells and methods of improving titer in transfection-based production systems using eukaryotic cells. Another coauthor patents related to Fibronectin for gene transfer. Another coauthor reports receiving fees from GlaxoSmithKline. The other authors have disclosed no relevant financial relationships.

N Engl J Med. 2014;371:1407-1417. Abstract

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