ASH Annual Meeting and Exposition

ASH Annual Meeting and Exposition

December 09, 2013
2 min read

Novel gene therapy prompted T-cell recovery in SCID-X1

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NEW ORLEANS — Boys with X-linked severe combined immunodeficiency treated with a self-inactivating gammaretroviral vector demonstrated gene transfer and T cell reconstitution without demonstrating risk for leukemogenesis, according to study results presented at the ASH Annual Meeting and Exposition.

X-linked severe combined immunodeficiency (SCID-X1), also known as “bubble boy” disease, is a fatal genetic disease in which mutations in the gamma subunit of the IL‐2 receptor cause the absence of T lymphocytes and natural killer cells.


Sung-Yun Pai

Sung-Yun Pai, MD, a pediatric hematologist-oncologist at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, and colleagues tested a self-inactivating gammaretroviral vector to promote T cell reconstitution in nine boys with SCID-X1.

They developed the gene therapy by removing the murine leukemia virus (MLV) long-terminal repeat U3 region and driving expression of the gamma chain by an intronless elongation factor 1 alpha promoter.

Pai and colleagues developed the gene therapy in response to results of previous trials in Europe, which evaluated an MLV–based gammaretroviral vector in 20 boys with SCID-X1. Of them, five developed insertional oncogenesis leading to leukemia.

“The work in the Paris and London group show that the mechanism by which this occurred is that the MFG gamma-c —or the SCID-1 vector — had inserted into regions close to proto-oncogenes, such as LMO2,” Pai said during a press conference. “These regions were driving the expression of the neighboring oncogenes. So we sought in this work to try to modify the original parent vector itself and make it equally efficacious but hopefully safer.”

The current study evaluated the modified SCID-2 vector in nine out of a total of 20 planned patients (age range, 3.9 months to 10.5 months).

One patient died from a pre‐existing adenovirus infection. Another patient did not engraft gene marked cells and received transplant.

Follow-up ranged from 5 months to 32 months for seven eligible patients.

Five of the seven patients (71%) achieved CD3+ T cell count ˃300 /microliter.

The other two patients received CD34+ cells with the lowest vector copy number.

Seven patients had a phytohemagglutinin-stimulation index ˃15 at or before 6 months (median 85.5; range, 0.2-224).

Pai and colleagues found no significant differences between T-cell recovery at 6 months between the current study and the earlier Paris and London study (P=.4).

However, there were significantly more integrations near lymphoid proto‐oncogenes with SCID-1 vs. SCID-2 (P=0.003).

“So long as the efficacy in the whole cohort is confirmed and no leukemia develops, our trial will expand the therapeutic options for babies with X-linked SCID, particularly ones who lack matched donors, and allow them to be cured without any risk of graft-versus-host disease or immunologic rejection,” Pai told HemOnc Today.

For more information:

Hacein-Bey-Abina A. Abstract #715. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2013; New Orleans.

Disclosure: The researchers report royalties from patents licensed to Transatlantic Gene Therapy Consortium.