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Foamy Viral Vector Integration Sites in SCID-Repopulating Cells After MGMTP140K-Mediated in Vivo Selection

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Foamy Viral Vector Integration Sites in SCID-Repopulating Cells After MGMTP140K-Mediated in Vivo Selection Gene Therapy (2015) 22, 591–595 © 2015 Macmillan Publishers Limited All rights reserved 0969-7128/15 www.nature.com/gt SHORT COMMUNICATION Foamy viral vector integration sites in SCID-repopulating cells after MGMTP140K-mediated in vivo selection ME Olszko1, JE Adair2, I Linde1,DTRae1, P Trobridge1, JD Hocum1, DJ Rawlings3, H-P Kiem2 and GD Trobridge1,4 Foamy virus (FV) vectors are promising for hematopoietic stem cell (HSC) gene therapy but preclinical data on the clonal composition of FV vector-transduced human repopulating cells is needed. Human CD34+ human cord blood cells were transduced with an FV vector encoding a methylguanine methyltransferase (MGMT)P140K transgene, transplanted into immunodeficient NOD/SCID IL2Rγnull mice, and selected in vivo for gene-modified cells. The retroviral insertion site profile of repopulating clones was examined using modified genomic sequencing PCR. We observed polyclonal repopulation with no evidence of clonal dominance even with the use of a strong internal spleen focus forming virus promoter known to be genotoxic. Our data supports the use of FV vectors with MGMTP140K for HSC gene therapy but also suggests additional safety features should be developed and evaluated. Gene Therapy (2015) 22, 591–595; doi:10.1038/gt.2015.20; published online 19 March 2015 INTRODUCTION Here we examined clonality and retroviral insertion sites (RIS) of Retroviral vectors derived from the foamy viruses (FVs) efficiently FV vectors in human SCID-repopulating cells after in vivo selection. transduce hematopoietic stem cells (HSCs) and are promising for use in HSC gene therapy.1 One challenge for HSC gene therapy is that some diseases like hemoglobinopathies require high RESULTS AND DISCUSSION percentages of gene-marked cells in order to achieve therapeutic Our goal was to investigate the genotoxicity of FV vectors in the correction. One strategy to overcome low marking is to engineer context of in vivo selection in human hematopoietic cells. Gene vectors with drug resistance genes that can be used to modified SCID-repopulating cells were selected in vivo using O6BG chemoselect gene-modified cells in vivo. Alkylating agents bis- and BCNU, which has the potential to increase genotoxic risk.6 For chloroethylnitrosourea (BCNU) and temozolomide damage cells this study we used the strong spleen focus forming virus (SFFV) 6 by forming toxic O -guanine DNA adducts. These lesions are promoter, which has a high potential to contribute to vector 6 normally repaired by the gene product of cellular O -methylgua- genotoxicity by dysregulating host genes near integrated vector 6 6 nine-DNA-methyltransferase (MGMT). O -Benzylguanine (O BG) proviruses.17 This approach, with a genotoxic strong viral 2 efficiently inactivates the gene product of wild-type MGMT, but promoter and in vivo selection to enhance the proliferation, can 3 not the MGMTP140K mutant. be viewed as a worst case scenario to explore the genotoxicity of 6 Mutant MGMT genes encoding O BG-resistant proteins have FV vectors in human SCID-repopulating cells. been included in retroviral vectors as chemoselectable markers for transduced cells.4,5 Although MGMT-mediated chemoselection can effectively increase the proportion of gene-marked cells in a Xenotransplantation and in vivo selection of FV vector-transduced transplant recipient,5 in vivo selection pressures might also SCID-repopulating cells increase the genotoxic risk and promote clonal dominance.6 Thus FV vector FV-SMPGW-KO (Figure 1a) was concentrated to 1 × 108 it is important to evaluate the effect of chemoselection on transducing units (TU) per ml and used to transduce human clonality prior to the use of therapeutic vectors in the clinic. CD34+ cord blood cells, which were then transplanted into NOD/ The effect of MGMT-mediated chemoselection on clonality has SCID IL2Rγnull (NSG) mice. Vector exposed cells were maintained been studied in detail for gammaretroviral (GV) and lentiviral (LV) in vitro in liquid culture and in semisolid methylcellulose media for vectors. In vivo selection studies examining clonality have been colony forming unit (CFU) assay (Supplementary Figure 1). conducted in dogs (GV7–9;LV7,9), in humanized mice (LV10) and in Marking was 23.1% in liquid culture (Figure 1b) and 29% In the non-human primates (GV11;LV11,12). Clonality data has also been CFU assay, demonstrating efficient transduction of hematopoietic published for chemoselected human cells transduced with an progenitors. Plating efficiency in the CFU assay was high (15%), MGMTP140K expressing GV vector in a glioblastoma trial.13 indicating low vector cytotoxicity. MGMTP140K-mediated selection has been evaluated for FV During week 12 post transplant, marking and engraftment were vectors both in vitro14 and in animal models.14–16 However, to evaluated in bone marrow. Engraftment was 50% or greater in our knowledge, detailed clonality and integration site data for FV three out of four animals, similar to what has been previously vectors in human repopulating cells after chemoselection in vivo reported.18 Marking as a percentage of CD45+ cells was up to 6% are yet to be reported. (Supplementary Table 1). Marking levels in vivo may have been 1Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, USA; 2Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 3Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA and 4School of Molecular Biosciences, Washington State University, Pullman, Washington, USA. Correspondence: Professor GD Trobridge, Department of Pharmaceutical Sciences, Washington State University, PO Box 1495, 412 E. Spokane Falls Blvd., PBS 319, Spokane 99210-1495, WA, USA. E-mail: [email protected] Received 28 November 2014; revised 14 January 2015; accepted 10 February 2015; published online 19 March 2015 Foamy vector integration in SRC ME Olszko et al 592 Figure 2. Clonality in bone marrow and spleen. RIS ranked 1–10 by capture frequency are shown as white rectangles. All others are shown as black rectangles. Locations are indicated for the ten most frequently captured RIS in each sample. Abbreviations: chr, chromosome; M, mouse; RIS, retroviral insertion site. marrow and spleen of both mice that responded to the selection. Reads were processed by using the Vector Integration Site Analysis bioinformatics server24 to localize sites to the human genome. A total of 139 unique RIS were recovered (Figure 2). Bone marrow and spleen cell populations were polyclonal following the selection. There was no evidence of clonal dominance in any of Figure 1. Vector design and marking. (a) FV vector FV-SMPGW-KO. the tissues analyzed or in the combined set of all unique RIS Abbreviations: CAR, cis-acting region; EGFP, enhanced green (Figure 2). fluorescent protein; MGMT, MGMTP140K; P, phosphoglycerate kinase To determine whether RIS near particular gene classes were promoter; S, spleen focus forming virus promoter; W, woochuck b over-represented in our data, the nearest transcription start site hepatitis virus post-transcriptional regulatory element. ( ) Marking (TSS) within a 100-kb window of each RIS was tabulated, and a in CD34+ human cord blood cells exposed to FV vector and maintained in liquid culture for 6 days. (c) Marking in CD45+ bone gene ontology term enrichment analysis was performed by using the Database for Annotation, Visualization and Integrated marrow cells of two mice which responded to the selection. 25,26 (d) Representative flow cytometry data from mouse M2. Discovery (DAVID). In previous studies of LV and GV RIS in primate repopulating cells, RIS were enriched near genes involved in growth and survival.27 Here, there was no significant enrich- ment in vivo in any of the ontology terms analyzed negatively impacted by highly expressed MGMTP140K, as has 19 (Supplementary Table 2). been noted previously. We next compared our data to several successively larger lists of To select for transduced cells, mice were treated with a proto-oncogenes. These were, in order of list size: leukemia (682 chemotherapeutic regimen that selectively depletes cells not genes), the Retrovirus and Transposon Tagged Cancer Gene expressing MGMTP140K. During weeks 15–18 post transplant, 28 6 Database (RTCGD) and the Catalogue of Somatic Mutations in mice were treated three times with O BG and BCNU. Mice were 29 fi – Cancer (COSMIC) (943 genes), and The Network of Cancer Genes sacri ced during weeks 20 22 post transplant and bone marrow 4.0 (NCG 4.0) (2048 genes).30,31 For each of these lists, post- and spleen were collected. Of the four mice treated, we observed selection RIS were binned by distance to the nearest proto- clear evidence of selection in two animals (450% increase in + + oncogene TSS. RIS in each bin were then plotted as a percentage EGFP human CD45 cells) (Figures 1c and d, Supplementary Table of unique RIS (Figures 3a–c). The distributions were similar 1). In mouse M2, marking increased by 16-fold, and in mouse M4 between datasets and across oncogene lists. When all RIS in marking increased by more than 50% in response to selection. proto-oncogene transcripts or within 50 kb of proto-oncogene TSS Selection in these mice was comparable to previously were considered together, the distribution of in vivo RIS was published studies in mouse models using GV, LV and FV vectors, significantly different (Po0.05) from random for NCG 4.0 where EGFP increased by 50%—30-fold relative to preselection – oncogenes (Figure 3d), but not for Leukemia or RTCGD+COSMIC expression.10,14,19 21 Mouse M1 had low engraftment and was not oncogenes. When in vivo RIS were ranked by recovery frequency analyzed. Mouse M3 had high engraftment and low marking and and divided into high, mid, and low thirds (Supplementary Table did not respond to the chemoselection. It is not clear to us why 3), RIS in the highest third were significantly enriched in or near marking did not increase in this animal. However, it has been NCG 4.0 proto-oncogenes when compared to RIS in the lowest suggested that MGMTP140K expressed from the SFFV promoter third (Figure 3d).
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