Plerixafor Single Agent for Autologous Stem Cells Mobilization and Collection in Adult Thalassemic Patients: Towards the Assessment of the Suitable Hematopoietic Stem Cell Source for Gene Therapy of Beta-Thalassemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 586-586
Author(s):  
Marta Claudia Frittoli ◽  
Bernhard Gentner ◽  
Maria Rosa Lidonnici ◽  
Annamaria Aprile ◽  
Laura Bellio ◽  
...  
Keyword(s):  
Stem Cells ◽  
Gene Therapy ◽  
Steady State ◽  
Peripheral Blood ◽  
Single Agent ◽  
Beta Thalassemia ◽  
Target Cells ◽  
Beta Globin ◽  
Hematopoietic Stem ◽  
Cd34 Cells

Abstract Abstract 586 Gene therapy of inherited blood diseases requires harvest of hematopoietic stem cells (HSCs) from patients and autologous transplantation of genetically modified cells. In order to achieve correction of the disease, high number of HSCs and previous conditioning of the host bone marrow (BM) are necessary. In the clinical application of gene therapy for thalassemic patients the choice of the HSC source is a crucial issue. On one side, the minimal target dose poses a challenge for the use of steady state BM since reinfusion of high numbers of beta globin gene modified CD34+ cells is probably necessary to gain sufficient correction of the genetic defect in order to achieve transfusion independency; on the other side, the disease related features and complications of thalassemic patients (i.e. splenomegaly and thrombophilia) dictate caution in the use of G-CSF as mobilizing agent. In April 2011 a clinical protocol exploring the use of Plerixafor (AMD3100) as single agent was started (“Plerixafor mobilized stem cells as source for gene therapy of beta-thalassemia”, acronym AMD-THAL, EudraCT2011-000973-30). Aims of the trial were to explore the ability of Plerixafor in inducing safe and effective stem cells mobilization in adult patients affected by beta-thalassemia, to characterize stem/progenitor cells mobilized from the BM and peripheral blood of treated subjects and to achieve gene transfer efficiency of mobilized CD34+ cells at a level comparable to that obtained using steady state BM. Four patients (01, 02, 03 and 04) were enrolled and already mobilized to date (August 2012). All patients are affected by transfusion dependent beta-thalassemia and aged 28 (01), 41 (02), 39 (03), 33 (04). Two are splenectomized (02 and 03); all subjects are regularly iron chelated with adequate organ function. Administration of Plerixafor subcutaneously as single agent and at the single dose of 0.24 mg/kg resulted in mobilization of CD34+ cells/mcl with a peak of 78 cells at 9 hrs (01), 70 cells at 7 hrs (02) and 69 cells at 8 hrs (03); suboptimal mobilization was observed in patient 04 (peak 18 at 8 hrs). Patient 03 received a second dose at 0.40 mg/kg 24 hrs after the first dose and underwent a second leucoapheretic procedure. Harvest by leukoapharesis resulted in procurement of the following CD34+ cells/kg: 1.84 × 106 (01) and 4.43 × 106 (02) with a unique leukoapheretic procedure, and 3.57 × 106 (03) with two leukoapheresis. No apheresis was performed for patient 04 because the minimum target of 20 CD34+ cells/mcl in peripheral blood was not reached. CD34+ cells selection through Clinimacs Miltenyi resulted in the following yield: 1.2 × 106 CD34+ cells/Kg, 65% recovery (01), 2.66 × 106 CD34+ cells/Kg, 60% recovery (02), 1.78 × 106 CD34+ cells/Kg, 50% recovery (03). No severe adverse event occurred. Recorded side effects were: grade 3 hypotension related to the apheretic procedure (01), mild grade 1 facial disestesia (02 and 04) and hyperleukocytosis (02: WBC from 13.6 to 42.6 × 103/mcl). In addition, steady state and Plerixafor primed BM aspirates were performed to analyze any modification in CD34+ concentration in the BM following Plerixafor administration. In fact, Plerixafor administration resulted in enrichment of CD34+ cells concentration in the BM. Purified CD34+ cells from leukoapheresis of the 4 treated patients were analyzed for their biological and functional properties, subpopulations composition and expression profile. In vivo reconstitution potential and lymphomyeloid differentiation of CD34+ cells were tested following transplantation in NSG mice. Experiments are ongoing but preliminary results indicate that cells mobilized by Plerixafor have a primitive phenotype with a high reconstitution potential and are efficiently transduced with a lentiviral based vector, named GLOBE, encoding for the human beta-globin (Roselli et al., 2010), thus being a suitable source of target cells for gene therapy. Disclosures: No relevant conflicts of interest to declare.

Retroviral transduction efficiency of G-CSF+SCF–mobilized peripheral blood CD34+ cells is superior to G-CSF or G-CSF+Flt3-L–mobilized cells in nonhuman primates

Blood ◽  
2003 ◽  
Vol 101 (6) ◽  
pp. 2199-2205 ◽  
Author(s):  
Peiman Hematti ◽  
Stephanie E. Sellers ◽  
Brian A. Agricola ◽  
Mark E. Metzger ◽  
Robert E. Donahue ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Peripheral Blood ◽  
Nonhuman Primates ◽  
Transduction Efficiency ◽  
Target Cells ◽  
Hematopoietic Stem ◽  
Retroviral Transduction ◽  
Peripheral Blood Cd34 ◽  
Cd34 Cells ◽  
Clinical Gene Therapy

Gene transfer experiments in nonhuman primates have been shown to be predictive of success in human clinical gene therapy trials. In most nonhuman primate studies, hematopoietic stem cells (HSCs) collected from the peripheral blood or bone marrow after administration of granulocyte colony-stimulating factor (G-CSF) + stem cell factor (SCF) have been used as targets, but this cytokine combination is not generally available for clinical use, and the optimum target cell population has not been systematically studied. In our current study we tested the retroviral transduction efficiency of rhesus macaque peripheral blood CD34+ cells collected after administration of different cytokine mobilization regimens, directly comparing G-CSF+SCF versus G-CSF alone or G-CSF+Flt3-L in competitive repopulation assays. Vector supernatant was added daily for 96 hours in the presence of stimulatory cytokines. The transduction efficiency of HSCs as assessed by in vitro colony-forming assays was equivalent in all 5 animals tested, but the in vivo levels of mononuclear cell and granulocyte marking was higher at all time points derived from target CD34+ cells collected after G-CSF+SCF mobilization compared with target cells collected after G-CSF (n = 3) or G-CSF+Flt3-L (n = 2) mobilization. In 3 of the animals long-term marking levels of 5% to 25% were achieved, but originating only from the G-CSF+SCF–mobilized target cells. Transduction efficiency of HSCs collected by different mobilization regimens can vary significantly and is superior with G-CSF+SCF administration. The difference in transduction efficiency of HSCs collected from different sources should be considered whenever planning clinical gene therapy trials and should preferably be tested directly in comparative studies.

Gene Therapy for Beta-Thalassemia: Preclinical Studies on Human Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5473-5473
Author(s):  
Giuliana Ferrari ◽  
Emanuela Roselli ◽  
Francesca Tiboni ◽  
Erica Biral ◽  
Sarah Marktel ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Genetically Modified ◽  
Beta Thalassemia ◽  
Beta Globin ◽  
Hematopoietic Stem ◽  
Molecular Defects ◽  
Globin Chains ◽  
Number Of Patients ◽  
Cd34 Cells ◽  
The Impact

Abstract Gene therapy for beta-thalassemia is based on the transplantation of genetically-modified autologous hematopoietic stem cells (HSC) into patients affected by the severe form of disease. The genetic treatment of the hemoglobinopathies poses the general challenge of efficient level of gene transfer into HSC and high and persistent transgene expression, in the differentiated progeny of a genetically modified stem cell. The validation of a gene therapy approach to thalassemia requires to obtain results of gene correction in a broad number of patients’ cells, since different molecular defects in the beta-globin gene lead to the clinical phenotype. The heterogeneity in the molecular defects and in the proportion of alpha and non-alpha (beta, gamma and delta) chains will represent a key element to set a threshold in the amount of vector-derived beta-chain required to correct a thalassemic phenotype. Additionally, the impact of some biological parameters, such as the degree of BM erythroid hyperplasia, the BM subpopulations proportion and the apoptotic index, on the successful correction of thalassemic phenotype needs to be studied in the perspective of clinical translation. In order to address these issues, we collected samples from BM aspirates and isolated CD34+ cells from 25 beta+ and beta0 thalassemic patients, characterized by different genotypes and biochemical profiles of globin chains synthesis. A novel, erythroid specific LV expressing human beta-globin from a minimal promoter enhanced by only 2 LCR elements (HS2 and HS3) was used to transduce BM derived CD34+ cells at high efficiency (>80%). The efficacy of the beta-globin LV in correcting the human thalassemic phenotype was tested in an in vitro model of erythropoiesis and in the human-mouse hematological chimera. Upon transduction, normal level of HbA expression was achieved in erythroblastic cultures and BFU-E, associated with a progression towards erythroid maturation, which was impaired in mock-transduced thalassemic cells. Molecular analysis showed proviral integrity, with no detectable rearrangements and an average proviral copy number of 2.4. Analysis of specific globin chains proportion and contribution to phenotype correction in the context of different genotypes is under evaluation.

Integration-Mediated Activation of PRDM16 and HMGA2 in Multiple Clones without Adverse Hematopoietic Consequences Following Transplant of Autologous MGMTP140K Gene-Modified CD34+ Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2053-2053
Author(s):  
Jennifer E Adair ◽  
Brian C Beard ◽  
Grant Trobridge ◽  
Frederic Bushman ◽  
Maciej M Mrugala ◽  
...  
Keyword(s):  
Stem Cells ◽  
Gene Therapy ◽  
Bone Marrow ◽  
Frequency Analysis ◽  
Peripheral Blood ◽  
Hematopoietic Progenitor ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
Retrovirus Integration ◽  
Time Point

Abstract Abstract 2053 Drug resistance gene therapy with mutant MGMTP140K gene-modified hematopoietic CD34+ cells has been proposed to circumvent myelosuppression associated with alkylating agent chemotherapy; however, the safety of this approach has not yet been demonstrated. We have achieved successful engraftment of MGMTP140K gene-modified hematopoietic progenitor cells in 3 glioblastoma patients following BCNU (600mg/m2) conditioning, as part of a Phase I/II clinical study which includes post-transplant combination O6-benzylguanine (O6BG) and temozolomide (TMZ) chemotherapy. Two of these patients, one of whom remains alive with no evidence for disease progression at more than 2 years since diagnosis, received a total of 9 and 4 cycles of O6BG/TMZ chemotherapy, respectively. We observed transient increases in the number of circulating gene-modified white blood cells (WBCs) and granulocytes in these patients following each cycle. Analysis of CD34+ colony forming cells (CFCs) in peripheral blood revealed increases in the number of gene-modified CFCs over time and with multiple cycles of chemotherapy. Given this, we have conducted a longitudinal retroviral integration site (RIS) analysis in an attempt to identify any selective advantage for gene-modified clones following repeated O6BG/TMZ regimens. In the first patient, at day 200 following transplant, 2 separate RISs were identified, each mapping to the intronic region between exons 1 and 2 of the human PRDM16 gene, previously identified as being associated with insertional activation and clonal expansion in a gene therapy trial for X-linked chronic granulomatous disease (Ott et al 2006). Semi-quantitative capture site frequency analysis revealed that these 2 clones with PRDM16 integrations constituted >20% of the gene-modified cell pool, which included hundreds of RISs at this time point in this patient. Overall gene marking at this same time point was 39.9% of peripheral blood WBCs, indicating that as many as 8% of circulating WBCs arose from these two clones. In the second patient, 3 distinct RISs were identified mapping to the 3'untranslated region (UTR) of the HMGA2 gene, within a cluster of let-7 microRNA binding domains known to be responsible for post-transcriptional regulation of this gene product. While HMGA2-associated RISs have been reported in 2 other gene therapy trials for β-thalassemia (Cavazzana-Calvo et al 2010) and X-linked severe combined immunodeficiency syndrome (Wang et al 2010), the genomic loci of these RISs mapped to the third intron of this genomic sequence. Capture frequency analysis indicated that overall contribution of the most abundant HMGA2-associated clone identified in this study reached 5.2% of gene-modified peripheral blood WBCs at day 300 after transplant. Analysis of PRDM16 and HMGA2 transcripts in each patient's cells by reverse-transcriptase real-time PCR indicated increased transcription of these genes in peripheral blood and bone marrow WBCs. Analysis of WBC subsets in the first patient found PRDM16 RISs present in granulocyte and CD3+ blood cell lineages, suggesting these clones originated from multipotential gene-modified hematopoietic stem cells capable of differentiating despite PRDM16 transactivation. Furthermore, since discontinuation of chemotherapy, we have observed a steady decline in levels of both PRDM16 clones, with complete disappearance of one clone. Extended analysis of HMGA2 expression and clone tracking in WBC subsets of the second patient is currently under way. Importantly, analysis of both patients bone marrow demonstrated normal cytogenetics, with no evidence for MDS or leukemia by hematopathology and flow cytometry. We believe that these data, in combination with other clinical gene therapy studies identifying similar clones, indicate the PRDM16 and HMGA2 gene sequences as “hot-spots” for either initial retrovirus integration in CD34+ hematopoietic progenitor and stem cells, or as genomic loci where aberrant gene expression, as a result of retrovirus integration, is associated with increased cell proliferation. At this time, these observations suggest that in the absence of underlying genomic disease, in vivo fluctuations in PRDM16- and HMGA2-associated clones following transplant may be a common, clinically inconsequential phenomenon in retrovirus-mediated gene therapy targeting CD34+ cell populations for modification. Disclosures: No relevant conflicts of interest to declare.

The Challenge Of HSCs Procurement For Gene Therapy: Exploring Plerixafor As Mobilization Agent

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2901-2901
Author(s):  
Maria Rosa Lidonnici ◽  
Annamaria Aprile ◽  
Marta Claudia Frittoli ◽  
Giacomo Mandelli ◽  
Bernhard Gentner ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Peripheral Blood ◽  
Conflicts Of Interest ◽  
Transduction Efficiency ◽  
Beta Thalassemia ◽  
Hematopoietic Stem ◽  
Cell Dose ◽  
Nsg Mice ◽  
Molecular Features ◽  
Cd34 Cells

Abstract Successful gene therapy of inherited blood diseases relies on transplantation and engraftment of autologous genetically engineered hematopoietic stem/progenitor cells (HSPCs) in myeloablated patients. Hematopoietic reconstitution and clinical benefit are related to cell dose, although single disease features might play a role favoring selection of relevant progenitor populations. Gene therapy trials in young pediatric patients are performed isolating CD34+ cells from bone marrow (BM), while in adults mobilized peripheral blood stem cells (PBSC) should represent the favorite target. In the context of gene therapy for thalassemia, the choice of HSPC source is crucial since intrinsic characteristics of patients (splenomegaly and thrombophilia) dictate caution in the use of G-CSF as mobilization agent and prompt investigation of new agents. Moreover, adult thalassemic patients may possibly have a decreased BM stem cell reservoir, due to the BM suppression in response to multiple transfusions. A phase II clinical protocol exploring the use of Plerixafor as a single mobilizing agent in adult patients affected by transfusion dependent beta-thalassemia (EudraCT 2011-000973-30) started in 2012 at our hospital. Plerixafor selectively and reversibly antagonizes the binding of SDF-1 to its receptor CXCR4 with subsequent egress of HSCs to the peripheral blood. The availability of a new source of HSPCs, potentially superior in terms of CD34+ cell yield, transduction efficiency and biological features to steady-state BM, would have a significant impact on the feasibility and efficacy of gene therapy. Four subjects were enrolled and treated by subcutaneously administration of Plerixafor at the single dose of 0.24 mg/kg followed by leukoapheresis. Mobilization of CD34+ cells occurred very rapidly with a peak between 7 to 9 hrs. Three out of four patients achieved the minimal target cell dose (2 x 106 cells/kg) and no severe adverse event occurred. To the aim of engineering Plerixafor-mobilized CD34+ cells for gene therapy, we performed a comprehensive characterization of their biological, molecular and functional properties. In vivo reconstitution potential and lympho-myeloid differentiation were tested following transplantation in NSG mice and compared to those of PBSCs mobilized by G-CSF. Percentages of engrafted human cells in NSG mice transplanted with Plerixafor -PBSCs were about 2- to 5-fold higher than those found in mice transplanted with G-CSF PBSCs. On the same line, the SRC frequency, obtained by pooled engraftment data, was significantly higher (1 SRC out of 47.875 CD34+ cells vs.1 SRC out of 141.203 CD34+ cells). The phenotypic analysis of the frequency of primitive hematopoietic sub-populations revealed that Plerixafor mobilizes preferentially HSPCs and LT-HSPCs, with a percentage of CD34+ CD38-/low CD90+ CD45RA- CD49f+ cells higher than that found in G-CSF PBSCs. This result mirrors the enhanced number of SRCs found in the CD34+ cell population mobilized by Plerixafor. In order to further define the molecular features of HSPCs from different sources, we are studying signalling networks in response to specific cytokines by phospho-proteins analysis and gene expression by microarrays analysis. Our studies are focused on self-renewal, homing, engraftment and multilineage differentiation processes and bioinformatic analysis will reveal the molecular machinery underlying 'stemness' properties of Plerixafor mobilized cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Long-term repopulating hematopoietic stem cells and “side population” in human steady state peripheral blood

2013 ◽  
Vol 11 (1) ◽  
pp. 625-633 ◽  
Author(s):  
Philippe Brunet de la Grange ◽  
Marija Vlaski ◽  
Pascale Duchez ◽  
Jean Chevaleyre ◽  
Veronique Lapostolle ◽  
...  
Keyword(s):  
Stem Cells ◽  
Steady State ◽  
Hematopoietic Stem Cells ◽  
Peripheral Blood ◽  
Side Population ◽  
Hematopoietic Stem

Direct Comparison of Steady-State Marrow, Primed Marrow, and Mobilized Peripheral Blood for Transduction of Hematopoietic Stem Cells in Dogs

2003 ◽  
Vol 14 (17) ◽  
pp. 1683-1686 ◽  
Author(s):  
Bobbie Thomasson ◽  
Laura Peterson ◽  
Jesse Thompson ◽  
Martin Goerner ◽  
Hans-Peter Kiem
Keyword(s):  
Stem Cells ◽  
Steady State ◽  
Hematopoietic Stem Cells ◽  
Peripheral Blood ◽  
Hematopoietic Stem ◽  
Mobilized Peripheral Blood

Human Embryonic Stem Cell (hESC)-Derived Hematopoietic Elements Are Capable of Engrafting Primary as well as Secondary Fetal Sheep Recipients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2685-2685
Author(s):  
A. Daisy Narayan ◽  
Jessica L. Chase ◽  
Adel Ersek ◽  
James A. Thomson ◽  
Rachel L. Lewis ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Peripheral Blood ◽  
Fetal Sheep ◽  
Hematopoietic Stem ◽  
Blood Samples ◽  
Human Dna ◽  
Cd34 Cells ◽  
Hematopoietic Activity

Abstract We used transplantation into 10 and 20 pre-immune fetal sheep recipients (55–65 days-old, term: 145 days) to evaluate the in vivo potential of hematopoietic elements derived from hESC. The in utero human/sheep xenograft model has proven valuable in assessing the in vivo hematopoietic activity of stem cells from a variety of fetal and post-natal human sources. Five transplant groups were established. Non-differentiated hESC were injected in one group. In the second and third group, embroid bodies differentiated for 8 days were injected whole or CD34+ cells were selected for injection. In the fourth and fifth group, hESC were differentiated on S17 mouse stroma layer and injected whole or CD34+ cells were selected for injection. The animals were allowed to complete gestation and be born. Bone marrow and peripheral blood samples were taken periodically up to over 12 months after injection, and PCR and flowcytometry was used to determine the presence of human DNA/blood cells in these samples. A total of 30 animals were analyzed. One primary recipient that was positive for human hematopoietic activity was sacrificed and whole bone marrow cells were transplanted into a secondary recipient. We analyzed the secondary recipient at 9 months post-injection by PCR and found it to be positive for human DNA in its peripheral blood and bone marrow. This animal was further challenged with human GM-CSF and human hematopoietic activity was noted by flowcytometry analyses of bone marrow and peripheral blood samples. Further, CD34+ cells enriched from its bone marrow were cultured in methylcellulose and human colonies were identified by PCR. We therefore conclude that hESC are capable of generating hematopoietic cells that engraft in 1° sheep recipients. These cells also fulfill the criteria for long-term engrafting hematopoietic stem cells as demonstrated by engraftment and differentiation in the 20 recipient.

Therapeutic Effect of HOXB4-Expanded Stem Cells in Mice with Beta Thalassemia Given a Non-Myeloablative Conditioning Regimen.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 341-341
Author(s):  
Silvia Bakovic ◽  
Patricia M. Rosten ◽  
Connie J. Eaves ◽  
R. Keith Humphries
Keyword(s):  
Stem Cells ◽  
Gene Therapy ◽  
Ex Vivo ◽  
Globin Gene ◽  
Conditioning Regimen ◽  
Beta Thalassemia ◽  
Mouse Bone Marrow ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem

Abstract The ultimate promise of gene therapy for patients with hemoglobinopathies depends on the development of safe strategies for achieving 2 goals. One is to obtain efficient and permanent correction of the gene defect in autologous hematopoietic stem cells (HSCs). The second is to develop methods for the pre-transplant amplification of transduced HSCs to high levels to ensure that they will outcompete the large residual endogenous HSC population remaining in non-myeloablated hosts (e.g. previous experiments have shown that a minimum of ~5 × 106 normal adult mouse bone marrow (BM) cells (~500 HSC) is required to achieve a level of chimerism of 20% in mice given 200 cGy). The ability of HOXB4 to promote HSC self-renewal divisions in short term culture prior to their use as transplants offers an attractive approach to achieve this latter goal. As a first test we transduced day-4 5FU BM cells from normal mice with a MSCV-HOXB4-IRES-GFP or control MSCV-IRES-GFP virus and then transplanted the cells either before or after 7 days maintenance in vitro into normal recipients given 250 cGy. Mice transplanted with an estimated 50 HSCs immediately after transduction with either virus reached equivalent low levels of chimerism (~10%) showing that HOXB4 does not impart an in vivo selective growth advantage under sublethal conditions. After ex vivo culture, the GFP transduced cells yielded an even lower level of chimerism (~5%), in contrast recipients of cultured HOXB4-transduced cells attained much higher stable levels of lympho-myeloid chimerism (~50%), indicative of a marked expansion of the HSCs pre-transplant and their retention of robust competitive repopulating potential. We then applied this approach to a gene therapy model of severe β-thalassemia in mice bearing a homozygous deletion of the β-major globin gene (β-MDD). To model a transplant of genetically corrected cells, BM cells were harvested from day-4 5FU pre-treated congenic wild-type donors and transduced with the HOXB4 virus. Cells were then cultured for 10 days and the progeny of 200K starting cells transplanted into 3 β-MDD and 4 normal recipients given 200 cGy. Transplantation of 500K freshly harvested day-4 5FU BM cells into 4 similarly conditioned control mice failed to produce significant chimerism (1–3% at 5 months). In contrast, all 4 control recipients of ex vivo expanded HOXB4-transduced cells exhibited significant stable chimerism (21±6% at 5 months). Similar levels of chimerism were also achieved in all 3 β-MDD recipients (18–76%), one of which was sustained at 34% at 5 months (52% in the RBCs). This was associated with substantial improvement in the Hct (36% vs 23% in untreated β-MDD), Hb (10.5 vs 5 g/dl) and RBC morphology. Southern blot analyses performed on 53 individual in vitro-expanded myeloid colonies generated from FACS-selected GFP+ marrow cells from this mouse 2 months post-transplant showed 19 distinct integration patterns indicating reconstitution from polyclonal expanded HSCs. This conclusion was further confirmed by proviral integration site analyses, which identified 13 separate integration sites from 9 colonies that had unique proviral patterns. These data demonstrate the curative potential of ex vivo expanded HSCs in a preclinical model of β-thalassemia treated with non-myeloablative conditioning. They also underscore the potential of HOXB4 as a potent tool to achieve the HSC expansions required.

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