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

Sadat, Mohammed; Dirscherl, Sara; Sastry, Lakshmi; Dantzer, Jessica; Pech, Nancy; Griffin, Susan; Hawkins, Troy; Zhao, Yongjun; Barese, Cecilia; Cross, Scott; Orazi, Attilio; An, Chao; Goebel, W. Scott; Yoder, Mervin C.; Li, X.; Grez, Manuel; Cornetta, Kenneth; Mooney, Sean D.; Dinauer, Mary C.

doi:10.1038/gt.2009.96

Cited by 9 publications

(9 citation statements)

References 50 publications

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“…39 Similarly, in clinical trials of GT for ADA-deficient SCID, patients with the longest period of neutropenia after conditioning with busulfan had the greatest frequency of gene-marked cells 19 and when 2 protocols were used, one with and without busulfan, marking is greatly improved with busulfan. It is important to note that radiation is not equivalent to busulfan, and that the possible effects of radiation should be considered when interpreting these results.…”

Section: Cytoreductive Conditioningmentioning

confidence: 99%

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Gene therapy/bone marrow transplantation in ADA-deficient mice: roles of enzyme-replacement therapy and cytoreduction

Carbonaro

Jin

Wang

et al. 2012

Blood

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AbstractGene therapy (GT) for adenosine deaminase–deficient severe combined immune deficiency (ADA-SCID) can provide significant long-term benefit when patients are given nonmyeloablative conditioning and ADA enzyme-replacement therapy (ERT) is withheld before autologous transplantation of γ-retroviral vector-transduced BM CD34+ cells. To determine the contributions of conditioning and discontinuation of ERT to the therapeutic effects, we analyzed these factors in Ada gene knockout mice (Ada−/−). Mice were transplanted with ADA-deficient marrow transduced with an ADA-expressing γ-retroviral vector without preconditioning or after 200 cGy or 900 cGy total-body irradiation and evaluated after 4 months. In all tissues analyzed, vector copy numbers (VCNs) were 100- to 1000-fold greater in mice receiving 900 cGy compared with 200 cGy (P < .05). In mice receiving 200 cGy, VCN was similar whether ERT was stopped or given for 1 or 4 months after GT. In unconditioned mice, there was decreased survival with and without ERT, and VCN was very low to undetectable. When recipients were conditioned with 200 cGy and received transduced lineage-depleted marrow, only recipients receiving ERT (1 or 4 months) had detectable vector sequences in thymocytes. In conclusion, cytoreduction is important for the engraftment of gene-transduced HSC, and short-term ERT after GT did not diminish the capacity of gene-corrected cells to engraft and persist.

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Section: Cytoreductive Conditioningmentioning

confidence: 99%

“…Ada Ϫ/Ϫ mice are particularly sensitive to the accumulation of adenosine in lung tissue, and perhaps extracellular ADA (ERT) is more efficacious than intracellular (GT) because extracellular adenosine-mediated signaling through G-coupled adenosine receptors has been implicated in the pulmonary phenotype. 39 …”

Section: Org Frommentioning

confidence: 99%

Gene therapy/bone marrow transplantation in ADA-deficient mice: roles of enzyme-replacement therapy and cytoreduction

Carbonaro

Jin

Wang

et al. 2012

Blood

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“…A possible concern is the unexpected finding that in partially ablated recipient mice, in which the BM is a more competitive environment for repopulation compared to the fully ablated marrow, HSCs carrying survival- or proliferation-activating lentiviral insertions had an advantage for engraftment, perhaps increasing the risk of leukemic progression. 228 …”

Section: Development Of Methodologies For the Genetic Manipulation Ofmentioning

confidence: 99%

Hematopoietic Stem Cell Gene Therapy: Assessing the Relevance of Preclinical Models

Larochelle

Dunbar

2013

Seminars in Hematology

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The modern laboratory mouse has become a central tool for biomedical research with a notable influence in the field of hematopoiesis. Application of retroviral-based gene transfer approaches to mouse hematopoietic stem cells (HSCs) has led to a sophisticated understanding of the hematopoietic hierarchy in this model. However, the assumption that gene transfer methodologies developed in the mouse could be similarly applied to human HSCs for the treatment of human diseases left the field of gene therapy in a decade-long quandary. It is not until more relevant humanized xenograft mouse models and phylogenetically related large animal species were used to optimize gene transfer methodologies that unequivocal clinical successes were achieved. However, the subsequent reporting of severe adverse events in these clinical trials casted doubts on the predictive value of conventional pre-clinical testing, and encouraged the development of new assays for assessing the relative genotoxicity of various vector designs.

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“…Thus, the SINfes.gp91s vector was able to protect animals from AF-induced inflammatory reactions PMNs were obtained from the indicated animals 7 months after transplantation. Gp91 phox was detected by Western blotting using the CL5 antibody (Sadat et al, 2009). Cell extracts from human PMN were used at different concentrations as control.…”

Section: Pharmacodynamic Studies: Correction Of the X-cgd Phenotype Bmentioning

confidence: 99%

From Bench to Bedside: Preclinical Evaluation of a Self-Inactivating Gammaretroviral Vector for the Gene Therapy of X-linked Chronic Granulomatous Disease

Stein

Scholz

Schwäble

et al. 2013

Human Gene Therapy Clinical Development

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Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by impaired antimicrobial activity in phagocytic cells. As a monogenic disease affecting the hematopoietic system, CGD is amenable to gene therapy. Indeed in a phase I/II clinical trial, we demonstrated a transient resolution of bacterial and fungal infections. However, the therapeutic benefit was compromised by the occurrence of clonal dominance and malignant transformation demanding alternative vectors with equal efficacy but safety-improved features. In this work we have developed and tested a self-inactivating (SIN) gammaretroviral vector (SINfes.gp91s) containing a codon-optimized transgene (gp91(phox)) under the transcriptional control of a myeloid promoter for the gene therapy of the X-linked form of CGD (X-CGD). Gene-corrected cells protected X-CGD mice from Aspergillus fumigatus challenge at low vector copy numbers. Moreover, the SINfes.gp91s vector generates substantial amounts of superoxide in human cells transplanted into immunodeficient mice. In vitro genotoxicity assays and longitudinal high-throughput integration site analysis in transplanted mice comprising primary and secondary animals for 11 months revealed a safe integration site profile with no signs of clonal dominance.

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

Cited by 9 publications

References 50 publications

Gene therapy/bone marrow transplantation in ADA-deficient mice: roles of enzyme-replacement therapy and cytoreduction

Gene therapy/bone marrow transplantation in ADA-deficient mice: roles of enzyme-replacement therapy and cytoreduction

Hematopoietic Stem Cell Gene Therapy: Assessing the Relevance of Preclinical Models

From Bench to Bedside: Preclinical Evaluation of a Self-Inactivating Gammaretroviral Vector for the Gene Therapy of X-linked Chronic Granulomatous Disease

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