Gammaretrovirus-mediated correction of SCID-X1 is associated with skewed vector integration site distribution in vivo

Schwarzwaelder, Kerstin; Howe, Steven J.; Schmidt, Manfred; Brugman, Martijn H.; Deichmann, Annette; Glimm, Hanno; Schmidt, Sonja; Prinz, Claudia; Wissler, Manuela; King, Douglas; Zhang, Fang; Parsley, Kathryn L.; Gilmour, Kimberly C.; Sinclair, Joanna; Bayford, Jinhua; Peraj, Rachel; Pike-Overzet, Karin; Staal, Frank J. T.; Ridder, Dick de; Kinnon, Christine; Abel, Ulrich; Wagemaker, Gerard; Gaspar, H. Bobby; Thrasher, Adrian J.; Kalle, Christof von

doi:10.1172/jci31661

Cited by 192 publications

(172 citation statements)

References 33 publications

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“…5 Genes encoding proteins with kinase or transferase activity, or involved in phosphorus metabolism, were over-represented in post-thymic CD3 + T cells as compared with CD34 + progenitor cell populations. 6 These findings support the notion that the genomic site of retroviral integration influences the survival potential of transduced cells, as well as their ability to engraft, differentiate and expand. There remains considerable controversy whether insertional events alone account for mutagenesis in these patients, or whether signalling via the gc-transgene mediates transformation.…”

Section: Prospectssupporting

confidence: 74%

Progress and prospects: gene therapy for inherited immunodeficiencies

Qasim¹,

Gaspar²,

Thrasher³

2009

Gene Ther

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Section: Prospectssupporting

confidence: 74%

Progress and prospects: gene therapy for inherited immunodeficiencies

Qasim¹,

Gaspar²,

Thrasher³

2009

Gene Ther

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“…13 Clonal dominance was also observed in patients of the first chronic granulomatous disease (CGD) gene therapy trial, in association with insertions in genes encoding HSC-associated transcription factors and proto-oncogenes MDS-EVI1, PRDM16 and SETBP1, 4 and similar observations were made in other clinical trials. [14][15][16] Efforts are being made to develop 'safer' retroviral vectors that are less capable of activating neighboring cellular genes. Using a novel in-vitro immortalization assay, we showed that the deletion of the U3 region in the viral LTRs and the use of the same enhancer/promoter as internal promoter in a 'selfinactivating' (SIN) architecture rendered the vector less transforming.…”

Section: Introductionmentioning

confidence: 99%

Leukemia induction after a single retroviral vector insertion in Evi1 or Prdm16

et al. 2008

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Insertional activation of cellular proto-oncogenes by replication-defective retroviral vectors can trigger clonal dominance and leukemogenesis in animal models and clinical trials. Here, we addressed the leukemogenic potential of vectors expressing interleukin-2 receptor common c-chain (IL2RG), the coding sequence required for correction of X-linked severe combined immunodeficiency. Similar to conventional c-retroviral vectors, self-inactivating (SIN) vectors with strong internal enhancers also triggered profound clonal imbalance, yet with a characteristic insertion preference for a window located downstream of the transcriptional start site. Controls including lentivirally transduced cells revealed that ectopic IL2RG expression was not sufficient to trigger leukemia. After serial bone marrow transplantation involving 106 C57Bl6/J mice monitored for up to 18 months, we observed leukemic progression of six distinct clones harboring c-retroviral long terminal repeat (LTR) or SIN vector insertions in Evi1 or Prdm16, two functionally related genes. Three leukemic clones had single vector integrations, and identical clones manifested with a remarkably similar latency and phenotype in independent recipients. We conclude that upregulation of Evi1 or Prdm16 was sufficient to initiate a leukemogenic cascade with consistent intrinsic dynamics. Our study also shows that insertional mutagenesis is required for leukemia induction by IL2RG vectors, a risk to be addressed by improved vector design.

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“…In all five cases (n ¼ 4 in the Paris, n ¼ 1 in the London trial), T-cell acute lymphoblastic leukemia occurred as a direct consequence of insertional mutagenesis by the retroviral vector used to deliver the therapeutic gene. [59][60][61] It is hoped that the development of novel vectors, especially those in which the viral promoter/ enhancer sequences have been rendered inactive (self-inactivating vectors), will significantly reduce the incidence of insertional mutagenesis. This will likely promote the safety and thus further clinical development of cells that are genetically modified.…”

Section: Genetic Modification Of Hscsmentioning

confidence: 99%

Stem cell self-renewal: lessons from bone marrow, gut and iPS toward clinical applications

et al. 2011

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The hematopoietic stem cell (HSC) is the prototype organregenerating stem cell (SC), and by far the most studied type of SC in the body. Currently, HSC-based therapy is the only routinely used SC therapy; however, advances in the field of embryonic SCs and induced pluripotent SCs may change this situation. Interest into in vitro generation of HSCs, including signals for HSC expansion and differentiation from these more primitive SCs, as well as advances in other organ-specific SCs, in particular the intestine, provide promising new applications for SC therapies. Here, we review the basic principles of different SC systems, and on the basis of the experience with HSC-based SC therapy, provide recommendations for clinical application of emerging SC technologies.

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Gammaretrovirus-mediated correction of SCID-X1 is associated with skewed vector integration site distribution in vivo

Cited by 192 publications

References 33 publications

Progress and prospects: gene therapy for inherited immunodeficiencies

Progress and prospects: gene therapy for inherited immunodeficiencies

Leukemia induction after a single retroviral vector insertion in Evi1 or Prdm16

Stem cell self-renewal: lessons from bone marrow, gut and iPS toward clinical applications

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