Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1

  title={Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1},
  author={Marion Gabriele Ott and Manfred Schmidt and Kerstin Schwarzwaelder and Stefan Stein and Ulrich Siler and Ulrike Koehl and Hanno Glimm and Klaus Kühlcke and Andrea J Schilz and Hana Kunkel and Sonja Naundorf and Andrea Brinkmann and Annette Deichmann and Marlene Fischer and Claudia R. Ball and Ingo H. Pilz and Cynthia E. Dunbar and Yang Du and Nancy A. Jenkins and Neal G. Copeland and Ursula Lüthi and Moustapha Hassan and Adrian J. Thrasher and Dieter Hoelzer and Christof von Kalle and Reinhard A. Seger and Manuel Grez},
  journal={Nature Medicine},
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… 

Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease

It is shown that forced overexpression of EVI1 in human cells disrupts normal centrosome duplication, linking EVI 1 activation to the development of genomic instability, monosomy 7 and clonal progression toward myelodysplasia.

Hematopoietic Tumors in a Mouse Model of X-linked Chronic Granulomatous Disease after Lentiviral Vector-Mediated Gene Therapy

MDS1/EVI1 and PRDM16 deregulation in hematopoiesis after experimental and clinical gene transfer

  • Wei Wang
  • Biology
  • 2012
This first ever large scale IDLV integration analyses yielded more than 800 unique, mappable IDLV ISs in vitro, and provided direct molecular evidence that the background integration of D64V mutant IDLVs is not mediated by residual catalytic activity of the mutant integrase.

Lentiviral gene therapy for X-linked chronic granulomatous disease

Nine severely affected X-linked CGD patients who received ex vivo autologous CD34 + hematopoietic stem and progenitor cell-based lentiviral gene therapy following myeloablative conditioning received early evidence supporting its safety and efficacy in treating patients with X- linked chronic granulomatous disease.

Recent Advances in Gene Therapy and Modeling of Chronic Granulomatous Disease.

This review focuses on the application of gene therapy for the CGD, the limitations encountered in current clinical trials, advantages and disadvantages of endonucleases in gene correction and modeling with CRISPR/Cas9 approach.

Advances in the treatment of Chronic Granulomatous Disease by gene therapy.

These studies demonstrated the safety and limitations of gene transfer into hematopoietic stem cells of CGD patients using retroviral vectors and allowed partial correction of the granulocytic function with a significant clinical benefit in treated patients.

Gene therapy for chronic granulomatous disease.

Retroviral gene therapy for X-linked chronic granulomatous disease: results from phase I/II trial.

  • H. KangC. Bartholomae H. Ahn
  • Medicine, Biology
    Molecular therapy : the journal of the American Society of Gene Therapy
  • 2011
Overall, the gene transfer procedure did not produce any serious adverse effects and was able to convert a significant fraction of blood cells to biologically functional cells, albeit for a short period of time.

Retroviral vector integration in post-transplant hematopoiesis in mice conditioned with either submyeloablative or ablative irradiation

Findings support the concept that vector integration can confer a selection bias, and suggest that the intensity of the conditioning regimen may further influence the effects of vector integration on clonal selection in post-transplant engraftment and hematopoiesis.



Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy.

Ex vivo gene therapy with gamma(c) can safely correct the immune deficiency of patients with X-linked severe combined immunodeficiency and allow patients to have a normal life.

Variable correction of host defense following gene transfer and bone marrow transplantation in murine X-linked chronic granulomatous disease.

Host defense to these pathogens was improved in X-CGD mice even with correction of a limited number of neutrophils, and intact protection against bacterial pathogens required relatively greater numbers of oxidant-generating phagocytes compared to protection against A fumigatus.

Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease.

A gene therapy trial for SCID-X1 was initiated, based on the use of complementary DNA containing a defective gammac Moloney retrovirus-derived vector and ex vivo infection of CD34+ cells, which provided full correction of disease phenotype and clinical benefit.

Gene therapy of chronic granulomatous disease

Considering that low levels of superoxide generating activity are sufficient for normal host defense, the present experiments provide the basis for the development of a gene replacement therapy for the X-linked form of CGD.

Retroviral-mediated gene transfer of gp91phox into bone marrow cells rescues defect in host defense against Aspergillus fumigatus in murine X-linked chronic granulomatous disease.

It is suggested that expression of even low levels of recombinant gp91phox can substantially improve phagocyte function in X-CGD, although correction of very small percentage of phagocytes may not be sufficient for protection against A fumigatus.

Recurrent retroviral vector integration at the Mds1/Evi1 locus in nonhuman primate hematopoietic cells.

In an analysis of 702 integration sites in rhesus macaques that underwent transplantation up to 7 years earlier with autologous CD34+ cells transduced with amphotropic murine leukemia virus (MLV)-derived retroviral vectors containing marker genes, insertion into one locus, the Mds1/Evi1 region, was detected a total of 14 times in 9 animals.

Recurrent Retroviral Vector Integration at the MDS1-EVI1 Locus in Rhesus Long-Term Repopulating Hematopoietic Stem Cells.

The study suggest that the MDS1-EVI1 locus is particularly susceptible to retroviral integration but the competing hypothesis that proviral insertion within this region favors engraftment and long-term contributions to hematopoiesis will be difficult to eliminate.

Long-term correction of phagocyte NADPH oxidase activity by retroviral-mediated gene transfer in murine X-linked chronic granulomatous disease.

MSCV-based vectors for long-term expression of gp91(phox) based on the murine stem cell virus (MSCV) backbone may be useful for gene therapy of human CGD targeted at hematopoietic stem cells.

Enhanced host defense after gene transfer in the murine p47phox-deficient model of chronic granulomatous disease.

Stem-cell-directed ex vivo gene therapy is capable of restoring phagocyte oxidant-dependent host-defense function in this mouse model of a human immune-system disorder.