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01-09-2011 | Immunology | Article

Gene therapy promising in patients with SCID


Free abstract

MedWire News: Gene therapy effectively restores T-cell immunity and is associated with good long-term survival rates in patients with X-linked severe combined immunodeficiency (SCID-X1), researchers report.

Adrian Thrasher (University College London, UK) and colleagues explain that SCID-X1 is caused by mutations in the common cytokine receptor γ chain, which typically lead to complete absence of functional T and natural killer cell lineages as well as intrinsically compromised B-cell function.

"Although human leukocyte antigen (HLA)-matched hematopoietic stem cell transplantation (HSCT) is highly successful in SCID-X1 patients, HLA-mismatched procedures can be associated with prolonged immunodeficiency, graft-versus-host disease, and increased overall mortality," the researchers note.

Gene therapy may be an alternative to HSCT in patients with SCID-X1, and in the present study, Thrasher and co-authors report the outcomes of 10 children with molecularly defined SCID-X1 treated with such therapy at a median age of 10 months.

The children all received autologous CD34+ hematopoietic stem and progenitor cells transduced with a conventional gammaretroviral vector, but no myelosuppressive conditioning. They were maintained on prophylactic immunoglobulin and antibiotic support until immunologic recovery was observed.

At a median follow-up time of 80 months, all patients were alive and had a functional polyclonal T-cell repertoire, although some variability in function was observed. This may relate to cell dose, clinical condition at the time of treatment, and age, say the researchers.

By contrast, humoral immunity only partially recovered but was good enough to allow for withdrawal of immunoglobulin replacement in four of the 10 patients. However, three patients developed antibiotic-responsive acute pulmonary infection after discontinuation of antibiotic prophylaxis and/or immunoglobulin replacement.

In addition, one patient developed acute T-cell acute lymphoblastic leukemia, but maintained a polyclonal T-cell repertoire through chemotherapy and was in remission after 2.5 years of treatment.

Writing in the journal Science Translational Medicine, Thrasher and co-author conclude that "gene therapy offers a highly effective option for treatment of SCID-X1 when HLA-matched donors are unavailable and provides long-term reconstitution of a polyclonal T cell repertoire that effectively restores clinical immunity."

They add that the additional use of myelosuppression should be considered to ensure long-term functional B-cell reconstitution.

In a second paper, also published in Science Translational Medicine, members of the same research group, this time led by Bobby Gaspar (University College London), describe the outcome of six children with adenosine deaminase-deficient SCID (ADA-SCID) who underwent similar gene therapy to the children with X1-SCID.

These children received autologous CD34+ hematopoietic bone marrow stem and progenitor cells transduced with a gammaretroviral vector encoding the human ADA gene.

Following treatment, all patients stopped enzyme replacement therapy, and four of the six recovered immune function as a result of the gene therapy. Three of these four patients discontinued immunoglobulin replacement, and all showed effective metabolic detoxification, the researchers note.

Furthermore, all patients were alive and remained free of infection during a median follow-up period of 43 months, with no adverse leukemic side effects.

The journal's editors commented: "The promising results of these and similar studies, albeit with an increased risk of ALL in SCID-X1 patients, support the development of new safer and more efficient vectors for this and other kinds of gene therapy.

"Long-term follow-up of patient participants in early gene-therapy trials such as the ones described here is critical for scientists to decipher the parameters of success and failure for gene therapy in general-and for SCID-specific treatments to bubble over into the clinic."

By Laura Dean


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