Safe mobilization of CD34+ cells in adults with β-thalassemia and validation of effective globin gene transfer for clinical investigation

Boulad, Farid; Wang, Xiuyan; Qu, Jinrong; Taylor, Clare; Ferro, Leda; Karponi, Garyfalia; Bartido, Shirley; Giardina, Patricia J.; Heller, Glenn; Prockop, Susan E.; Maggio, Aurelio; Sadelain, Michel; Rivière, Isabelle

doi:10.1182/blood-2013-06-507178

Cited by 61 publications

(69 citation statements)

References 21 publications

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“…Autologous transplant of stem cells transduced with a corrective β-globin gene has been successful in a few patients (3,4), and larger clinical trials are in progress (5). However, the long-term safety of the known random viral integrations into multiple genomic sites needs to be determined (6,7). An alternate approach to modify the hematopoietic stem cells that does not use integrating viral vectors needs to be explored.…”

mentioning

confidence: 99%

Genome editing using CRISPR-Cas9 to create the HPFH genotype in HSPCs: An approach for treating sickle cell disease and β-thalassemia

Yan

Wang

Tan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

175

132

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Hereditary persistence of fetal hemoglobin (HPFH) is a condition in some individuals who have a high level of fetal hemoglobin throughout life. Individuals with compound heterozygous β-thalassemia or sickle cell disease (SCD) and HPFH have milder clinical manifestations. Using RNA-guided clustered regularly interspaced short palindromic repeats-associated Cas9 (CRISPR-Cas9) genome-editing technology, we deleted, in normal hematopoietic stem and progenitor cells (HSPCs), 13 kb of the β-globin locus to mimic the naturally occurring Sicilian HPFH mutation. The efficiency of targeting deletion reached 31% in cells with the delivery of both upstream and downstream breakpoint guide RNA (gRNA)-guided Staphylococcus aureus Cas9 nuclease (SaCas9). The erythroid colonies differentiated from HSPCs with HPFH deletion showed significantly higher γ-globin gene expression compared with the colonies without deletion. By T7 endonuclease 1 assay, we did not detect any off-target effects in the colonies with deletion. We propose that this strategy of using nonhomologous end joining (NHEJ) to modify the genome may provide an efficient approach toward the development of a safe autologous transplantation for patients with homozygous β-thalassemia and SCD.

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mentioning

confidence: 99%

Genome editing using CRISPR-Cas9 to create the HPFH genotype in HSPCs: An approach for treating sickle cell disease and β-thalassemia

Yan

Wang

Tan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

175

132

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“…63 These findings provided the basis for the implementation of the first gene therapy trial in the United States in patients with severe hereditary globin disorders. The trial (registered at ClinicalTrials.gov under NCT01639690) already started at the beginning of 2013 at MSKCC and it is a multicenter phase I/II clinical trial that involves other European centers including our own.…”

Section: Clinical Trialsmentioning

confidence: 97%

Development and Recent Progresses of Gene Therapy for β-Thalassemia

Acuto¹,

Baiamonte²,

Stefano³

et al. 2014

Thalassemia Reports

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“…The first consequence of dyserythropoiesis is the accumulation of erythroid progenitors; the bone marrow of patients suffering from b-thalassemia contains five to six times more erythroid precursors (primarily basophilic and polychromatophilic erythroblasts) than normal. The highly altered composition of HSPCs in this disease explains the initial failure of patients' bone marrow to provide an appropriate HSC harvest and thus the requirement for mobilization for gene transfer strategies [43,44]. The optimum regimen for restoring the balance between bone marrow HSPCs before harvesting has not been yet determined, and research on this topic is essential.…”

Section: Wiskott-aldrich Syndromementioning

confidence: 99%

Gene Therapy with Hematopoietic Stem Cells: The Diseased Bone Marrow's Point of View

Cavazzana

Ribeil

Lagresle-Peyrou

et al. 2017

Stem Cells and Development

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When considering inherited diseases that can be treated by gene transfer into hematopoietic stem cells (HSCs), there are only two in which the HSC and progenitor cell distribution inside the bone marrow and its microenvironment are exactly the same as in a healthy subject: metachromatic leukodystrophy (MLD) and adrenoleukodystrophy (ALD). In all other settings [X-linked severe combined immunodeficiency (X-SCID), adenosine deaminase deficiency, Wiskott-Aldrich syndrome, and b-hemoglobinopathies], the bone marrow content of the different stem and precursor cells and the cells' relationship with the stroma have very specific characteristics. These peculiarities can influence the cells' harvesting and behavior in culture, and the postgraft uptake and further behavior of the gene-modified hematopoietic/precursor cells. In the present mini-review, we shall briefly summarize these characteristics and outline the possible consequences and challenges.

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Safe mobilization of CD34+ cells in adults with β-thalassemia and validation of effective globin gene transfer for clinical investigation

Abstract: Key Points Safe mobilization of CD34+ cells in adults with β-thalassemia and effective transduction with a globin vector under cGMP conditions. Stable vector copy number and β-globin expression in BFU-Es derived from engrafted CD34+ HPCs 6 months post-transplant in NSG mice.

Cited by 61 publications

References 21 publications

Genome editing using CRISPR-Cas9 to create the HPFH genotype in HSPCs: An approach for treating sickle cell disease and β-thalassemia

Genome editing using CRISPR-Cas9 to create the HPFH genotype in HSPCs: An approach for treating sickle cell disease and β-thalassemia

Development and Recent Progresses of Gene Therapy for β-Thalassemia

Gene Therapy with Hematopoietic Stem Cells: The Diseased Bone Marrow's Point of View

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