Gene Therapy for Severe Combined Immunodeficiency

Jacquelyn K. Beals, PhD

August 26, 2011

August 26, 2011 — Long-term follow-up on children who received gene therapy for severe combined immunodeficiency (SCID) is described in 2 research articles published online August 24 in Science Translational Medicine. The clinical outcomes support gene therapy as a "viable alternative" to hematopoietic stem cell transplants (HSCT) from unrelated donors.

X-linked SCID (SCID-X1) is caused by mutations on the X chromosome that typically result in no functional T-cells and natural killer cells; B-cell function is also impaired. Children born with SCID-X1 live in a germ-free environment and have decreased life expectancy.

Adenosine deaminase (ADA)-deficient SCID results from genetic defects in an enzyme involved in purine metabolism. The build-up of toxins harms development of T cells, B cells, and natural killer cells, severely reducing their numbers. If immune function is not restored, children with ADA-deficient SCID may die in early infancy.

Both of these SCIDs are treatable by HSCT if a matched HSC donor can be found. Patients with ADA-SCID can also be treated with enzyme-replacement therapy (ERT), but immunological deficits are not fully corrected, so patients easily acquire infections. Less-than-optimal HSC matches may result in graft-vs-host disease, other morbidity, and mortality.

Early gene therapy trials were curtailed when patients too often developed leukemia. H. Bobby Gaspar, MD, professor of pediatrics and immunology, Centre for Immunodeficiency, Molecular Immunology Unit, Institute of Child Health, University College London, United Kingdom, and first author of both articles, explained in an email to Medscape Medical News why current viral vectors are safer.

"The gammaretroviral vectors that have potential for leukemia have intact viral promoter sequences with powerful enhancer elements that can activate nearby genes, in some cases oncogenes; hence the potential for leukemia," said Dr. Gaspar.

"The new vector designs have had the viral promoter sequences deleted, and instead the therapeutic gene is transcribed from an internal promoter, which does not have the ability to activate nearby genes. Simply put," Dr. Gaspar explained, "the new vectors are unable to 'turn on' nearby genes even if they are sitting next to them."

In the new study treating SCID-X1 with gene therapy, the 10 patients received the therapy at a median age of 10 months (the youngest patient was treated at 4 months and the oldest at 46 months). HSCs were removed from each patient and "repaired" by transduction (ie, delivery of corrected genes by a viral vector). Each patient was infused with his or her own transduced CD34+ HSCs and progenitor cells. No myelosuppression or immunosuppression was used.

All 10 children were alive after 54 to 107 months of follow-up and had functioning polyclonal T cells. Humoral immunity (reflecting B-cell function) recovered only partially, but 4 patients were able to cease immunoglobulin replacement permanently. One patient developed T-cell acute lymphoblastic leukemia but retained polyclonal T cells and is in remission after chemotherapy.

In the ADA-SCID gene therapy study, 6 children were treated at a median age of 36 months (range, 6 - 39 months). All had previously received ERT and had only partial recovery of immune function: lymphocyte counts lower than 1.5 × 106 per liter and/or requiring immunoglobulin G replacement therapy. All 6 patients ceased ERT 1 to 4 weeks before gene therapy and "received mild chemotherapy" before the gene therapy. As with the patients with SCID-X1, each patient's infusion contained his or her own genetically repaired CD34+ cells.

All 6 children treated for ADA-deficient SCID were alive after 24 to 84 months of follow-up. Four recovered their immune function, and 3 have not resumed ERT. The other 2 patients did not recover immune function, for "disease-specific and technical reasons," but resumed ERT and are doing well.

One difference between the ADA-SCID and SCID-X1 treatments is the use of "mild chemotherapy" in patients with ADA-SCID before gene therapy. "The survival advantage for gene-corrected T cells in [patients with SCID-X1] is so strong that there is no need for chemotherapy. If we put in even a small number of T cells, these will repopulate the T cell compartment," Dr. Gaspar said.

"In ADA-SCID, there is not such a powerful survival advantage, and so we think that using a small amount of [chemotherapy] will allow us to engraft a larger number of stem cells to allow lymphoid development to occur." However, Dr. Gaspar noted that mild chemotherapy might be useful in patients with SCID-X1 to achieve stem cell engraftment and have reliable B cell recovery.

A perspective piece in the same issue of Science Translational Medicine, coauthored by Donald B. Kohn, MD, professor, microbiology, immunology & molecular genetics, and pediatrics at the University of California–Los Angeles, summarizes the history of SCID gene therapy trials. One disturbing issue is the "leukemia-like T lymphoproliferation" seen in 5 of 20 patients with SCID-X1 across several studies, but in none of more than 30 patients with ADA-SCID treated with gene therapy.

The cause may lie in differences between the genes delivered by the viral vectors: The X-linked gene may provide proliferative signals, whereas the ADA gene confers no activation signals. The responses to gene therapy also have different timelines, with patients with SCID-X1 showing rapid increases in T cell populations in a few months, whereas the T cells of patients with ADA-SCID take more than 18 months to recover. "A plethora of explanations have been considered," say the authors.

Dr. Kohn's article describes efforts underway to develop "a next generation of...vectors designed for greater safety." In an email to Medscape Medical News, he described gene therapy research for other blood diseases: "X-adrenoleukodystrophy gene therapy, using a lentiviral vector, as done in Paris, was of similar efficacy [to] allogeneic HSCT," said Dr. Kohn, and "several trials for β-thalassemia and sickle cell are starting and may show some beneficial effects, like increase in hemoglobin levels."

On another front, "The lysosomal storage disease, Hurler's syndrome, is under study in a trial in Milan and has a strong theoretical potential to show efficacy."

If gene therapy is able to produce similar benefits with less morbidity, Dr. Kohn's article concludes that "gene therapy using autologous...HSCT could supplant allogeneic HSCT as the treatment of choice for these conditions."

Both studies were supported by the Department of Health, Wellcome Trust, Primary Immunodeficiency Association, Jeffrey Modell Foundation, Great Ormond Street Hospital Childrens Charity, National Institute for Health Research Biomedical Research Centre, and European Union. The study authors, including Dr. Gaspar, and Dr. Kohn have disclosed no relevant financial relationships.

Sci Transl Med. Published online August 24, 2011. X-linked study abstract, ADA study abstract, Perspective abstract

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