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Modified gene therapy shows promise in SCID-X1

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October 8, 2014

A majority of boys with X-linked severe combined immunodeficiency experienced T-cell recovery and infection clearance after undergoing gene therapy with a self-inactivating gamma-retrovirus vector, according to study results.

Salima Hacein-Bey-Abina, PharmD, PhD, of the department of biotherapy at Hôpital Necker – Enfants Malades in Paris, and colleagues sought to modify a Moloney murine leukemia virus-based gamma-retrovirus vector that expressed interleukin-2 receptor gamma-chain complementary DNA.

In a previous analysis, the retrovirus effectively restored immunity in patients with X-linked severe combined immunodeficiency (SCID-X1); however, a quarter of patients developed vector-induced leukemia.

Hacein-Bey-Abina and colleagues thus evaluated a modified, self-inactivating gamma-retrovirus vector in nine boys with SCID-X1. The boys received an infusion of autologous bone marrow–derived CD34+ cells transduced with the self-inactivating gamma-retrovirus vector. Median age at the time of infusion was 8 months.

Eight patients were alive at a median follow-up of 29.1 months (range, 12.1 to 38.7). One patient died 4 months after infusion due to a preexisting adenovirus infection.

One patient had no evidence of gene marking after treatment and underwent an umbilical-cord–blood transplant. The remaining seven patients exhibited gene marking in T cells and their T-cell proliferation returned to the normal range, leading to infection resolution. Six of these patients also had CD3+, CD4+ and CD8+ T-cell recovery.

Researchers noted the T-cell reconstitution demonstrated in this analysis was similar to the previous gamma-retrovirus vector results 6 months (P=.39) and 1 year (P=.28) after therapy.

No patients in the trial had developed leukemia by the time of the analysis.

“The self-inactivating gamma-retrovirus vector was compatible with high-titer vector production in a clinical setting, with good transduction efficiencies overall, leading to transgene expression that restored immunity in the majority of patients treated in this trial,” Hacein-Bey-Abina and colleagues wrote. “Specifically, we found that a modified gamma-retrovirus vector retained efficacy in the treatment of SCID-X1 through the generation of a functional polyclonal T-cell repertoire.”

Disclosure: See the study for a list of the researchers’ relevant financial disclosures.

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Suzanne Skoda-Smith

Suzanne Skoda-Smith

SCID-X1 is one of the more commonly encountered genetic forms of SCID, a condition characterized by lack of functional T cells and early mortality without immune restoring therapy. SCID-X1 accounted for 40% to 50% of the cases in Buckley’s cohort published in 2009, and in a recent publication that evaluated more than 3 million babies who underwent newborn screening for SCID from 2008 to 2013, SCID-X1 was found in 19% of infants detected by T-cell receptor excision circle (TREC) analysis (Kwan A. JAMA. 2014;312:729-738).
Initial attempts at gene therapy for SCID-X1 were complicated by a high rate (25%) of T-cell acute lymphoblastic leukemia, attributed to insertional oncogenesis of first-generation gamma-retroviral vectors producing transactivation of proto-oncogenes such as LMO2. This finding was in contrast to gene therapy trials for adenosine deaminase deficiency (ADA)-SCID that did not encounter genotoxicity.
This multicenter trial by Hacein-Bey-Abina and colleagues evaluated the safety and immunologic efficacy of a new self-inactivating gamma-retroviral vector in nine boys with SCID-X1 who lacked HLA-identical related or unrelated stem cell donors, or who had an active therapy-resistant infection at presentation. By the time of publication, all patients had been followed a median of 33 months, equaling the median time leukemias had been detected in previous trials. Eight of the nine had significant viral, mycobacterial or opportunistic infections at entry. One patient with a negative infectious history required subsequent cord blood transplantation for failure of immunologic reconstitution with gene therapy. Seven of the eight patients with infections were alive with resolution of their infections and evidence of T-cell reconstitution following gene therapy.
This study was not designed to include myelosuppressive preparatory chemotherapy, and as expected, B cells showed minimal levels of gene marking. All surviving patients continued on gammaglobulin replacement therapy. Hacein-Bey-Abina and colleagues demonstrated that safer vector design and enhanced monitoring of integration site distribution are ongoing strategies that must be addressed to achieve successful gene replacement for SCID.

Suzanne Skoda-Smith, MD
Seattle Children’s Hospital

Disclosure: Skoda-Smith reports no relevant financial disclosures.