Correction of X-linked Chronic Granulomatous Disease by Gene Therapy, Augmented by Insertional Activation of MDS1-EVI1, PRDM16 or SETBP1.

Marion G Ott; Manfred Schmidt; Kerstin Schwarzwaelder; Stefan Stein; Ulrich Siler; Ulrike Koehl; Hanno Glimm; Klaus Kühlcke; Andrea Schilz; Hana Kunkel; Sonja Naundorf; Andrea Brinkmann; Annette Deichmann; Marlene Fischer; Claudia Ball; Ingo Pilz; Cynthia Dunbar; Yang Du; Nancy A Jenkins; Neal G Copeland; Ursula Lüthi; Moustapha Hassan; Adrian J Thrasher; Dieter Hoelzer; Christof von Kalle; Reinhard Seger; Manuel Grez


Nat Med. 2006;12(4):401-409. 

In This Article

Abstract and Introduction

Gene transfer into hematopoietic stem cells has been used successfully for correcting lymphoid but not myeloid immunodeficiencies. Here we report on two adults who received gene therapy after nonmyeloablative bone marrow conditioning for the treatment of X-linked chronic granulomatous disease (X-CGD), a primary immunodeficiency caused by a defect in the oxidative antimicrobial activity of phagocytes resulting from mutations in gp91phox. We detected substantial gene transfer in both individuals' neutrophils that lead to a large number of functionally corrected phagocytes and notable clinical improvement. Large-scale retroviral integration site-distribution analysis showed activating insertions in MDS1-EVI1, PRDM16 or SETBP1 that had influenced regulation of long-term hematopoiesis by expanding gene-corrected myelopoiesis three- to four-fold in both individuals. Although insertional influences have probably reinforced the therapeutic efficacy in this trial, our results suggest that gene therapy in combination with bone marrow conditioning can be successfully used to treat inherited diseases affecting the myeloid compartment such as CGD.

The clinical successes achieved in three phase 1/2 gene therapy studies aiming at the correction of severe combined immunodeficiencies[1,2,3,4] was partially facilitated by a selective survival and growth advantage conferred by the therapeutic gene to lymphocyte precursor cells. For many hematopoietic disorders, however, particularly those in which gene expression is crucial for effector functionality of terminally differentiated cells, bone marrow conditioning or the use of an in vivo selectable marker gene are thought to be key requisites for efficient engraftment and survival of gene-transduced cells. In several clinical trials conducted without bone marrow conditioning, the engraftment rate of gene-modified cells has been generally low.[5,6,7,8,9] This also applies for CGD, a rare inherited immunodeficiency caused by mutations in any of four genes encoding subunits of the nicotinamide dinucleotide phosphate (NADPH) oxidase complex, resulting in lack of antimicrobial activity of phagocytes.[10,11,12,13] Almost 70% of CGD cases result from defects in the X-linked gene encoding gp91phox (X-CGD),[14] which together with p22phox forms the heterodimeric, membrane-associated flavocytochrome b558, the terminal redox center of the oxidase complex.[15] As hematopoietic stem cell (HSC) transplantation is usually indicated only for individuals with human leukocyte antigen (HLA)-matched donors,[16] a reasonable therapeutic alternative for individuals with CGD is the genetic modification of autologous HSCs. Although CGD has been successfully corrected in animal models by gene transfer in HSCs,[17,18,19] similar successes have not been achieved in humans with CGD.[5,8,9]

The recent occurrence of three severe adverse events encountered in one SCID-X1 trial[20] has highlighted the risks associated with the use of integrating viruses in gene therapy.[21,22] For X-CGD, this risk was estimated to be low because gp91phox is not known to provide a survival or growth advantage to transduced cells, and abnormal hematopoiesis or leukemogenesis have never been observed in animal models of X-CGD transplanted with gp91phox-expressing cells.[18,19,23]

Here we report on two adults with X-CGD who were treated with nonmyeloablative conditioning before the infusion of genetically modified cells. Sustained engraftment of functionally corrected cells with therapeutically relevant levels of superoxide production was unexpectedly followed by in vivo expansion of cell clones containing insertionally activated growth-promoting genes.


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