Advances and Obstacles in Homology-Mediated Gene Editing of Hematopoietic Stem Cells

Salisbury-Ruf, Christi; Larochelle, André

doi:10.3390/jcm10030513

Cited by 12 publications

(10 citation statements)

References 127 publications

(166 reference statements)

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“…Salisbury-Ruf and others have recently reviewed an extensive list of molecules used to modulate HDR in mammalian cells ( Salisbury-Ruf and Larochelle, 2021 ). Briefly, they classified these modulators in five categories: inhibitors of NHEJ proteins, promoters of HDR, modulators of the cell cycle, molecules targeting chromatin structure, and molecules with undefined mechanisms ( Salisbury-Ruf and Larochelle, 2021 ). Ex vivoex vivoin vivo .…”

Section: Methods To Improve Hdr-mediated Gene Editing In Hspcsmentioning

confidence: 99%

Hematopoietic stem and progenitors cells gene editing: Beyond blood disorders

et al. 2023

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Lessons learned from decades-long practice in the transplantation of hematopoietic stem and progenitor cells (HSPCs) to treat severe inherited disorders or cancer, have set the stage for the current ex vivo gene therapies using autologous gene-modified hematopoietic stem and progenitor cells that have treated so far, hundreds of patients with monogenic disorders. With increased knowledge of hematopoietic stem and progenitor cell biology, improved modalities for patient conditioning and with the emergence of new gene editing technologies, a new era of hematopoietic stem and progenitor cell-based gene therapies is poised to emerge. Gene editing has the potential to restore physiological expression of a mutated gene, or to insert a functional gene in a precise locus with reduced off-target activity and toxicity. Advances in patient conditioning has reduced treatment toxicities and may improve the engraftment of gene-modified cells and specific progeny. Thanks to these improvements, new potential treatments of various blood- or immune disorders as well as other inherited diseases will continue to emerge. In the present review, the most recent advances in hematopoietic stem and progenitor cell gene editing will be reported, with a focus on how this approach could be a promising solution to treat non-blood-related inherited disorders and the mechanisms behind the therapeutic actions discussed.

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Section: Methods To Improve Hdr-mediated Gene Editing In Hspcsmentioning

confidence: 99%

Hematopoietic stem and progenitors cells gene editing: Beyond blood disorders

et al. 2023

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“…In HSCs, the HDR template is typically delivered by vectors based on adeno-associated virus (AAV) ( 32 ) or in the form of single-stranded or double-stranded oligonucleotides (ODNs) ( 33 ). However, because HDR is restricted to the S/G2 phase of the cell cycle, achieving gene targeting frequencies that exceed 20% in mainly quiescent long-term repopulating HSCs remains challenging ( 34 ).…”

Section: Genome Editing To Treat Scdmentioning

confidence: 99%

Clinical genome editing to treat sickle cell disease—A brief update

Zarghamian

Klermund²,

Cathomen³

2023

Front. Med.

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Sickle cell disease (SCD) is one of the most common hemoglobinopathies. Due to its high prevalence, with about 20 million affected individuals worldwide, the development of novel effective treatments is highly warranted. While transplantation of allogeneic hematopoietic stem cells (HSC) is the standard curative treatment approach, a variety of gene transfer and genome editing strategies have demonstrated their potential to provide a prospective cure for SCD patients. Several stratagems employing CRISPR-Cas nucleases or base editors aim at reactivation of γ-globin expression to replace the faulty β-globin chain. The fetal hemoglobin (HbF), consisting of two α-globin and two γ-globin chains, can compensate for defective adult hemoglobin (HbA) and reverse the sickling of hemoglobin-S (HbS). Both disruption of cis-regulatory elements that are involved in inhibiting γ-globin expression, such as BCL11A or LRF binding sites in the γ-globin gene promoters (HBG1/2), or the lineage-specific disruption of BCL11A to reduce its expression in human erythroblasts, have been demonstrated to reestablish HbF expression. Alternatively, the point mutation in the HBB gene has been corrected using homology-directed repair (HDR)-based methodologies. In general, genome editing has shown promising results not only in preclinical animal models but also in clinical trials, both in terms of efficacy and safety. This review provides a brief update on the recent clinical advances in the genome editing space to offer cure for SCD patients, discusses open questions with regard to off-target effects induced by the employed genome editors, and gives an outlook of forthcoming developments.

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“…With the CRISPR/Cas9 technology, the possibility to perform ex-vivo targeted gene correction in primary CD34 + cells became a reality [51,52], and many laboratories are actively working to improve efficiency and safety of this technique to bring it to the clinic [53]. Clinical trials for the treatment of sickle cell disease and β-thalassemia are indeed ongoing (ClinicalTrials.gov #NCT03745287 and #NCT03655678).…”

Section: Gene Therapy Of Pluripotent Stem Cellsmentioning

confidence: 99%

Hematopoietic Cells from Pluripotent Stem Cells: Hope and Promise for the Treatment of Inherited Blood Disorders

Rao

Crisafulli

Paulis

et al. 2022

Cells

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Inherited blood disorders comprise a large spectrum of diseases due to germline mutations in genes with key function in the hematopoietic system; they include immunodeficiencies, anemia or metabolic diseases. For most of them the only curative treatment is bone marrow transplantation, a procedure associated to severe complications; other therapies include red blood cell and platelet transfusions, which are dependent on donor availability. An alternative option is gene therapy, in which the wild-type form of the mutated gene is delivered into autologous hematopoietic stem cells using viral vectors. A more recent therapeutic perspective is gene correction through CRISPR/Cas9-mediated gene editing, that overcomes safety concerns due to insertional mutagenesis and allows correction of base substitutions in large size genes difficult to incorporate into vectors. However, applying this technique to genomic disorders caused by large gene deletions is challenging. Chromosomal transplantation has been proposed as a solution, using a universal source of wild-type chromosomes as donor, and induced pluripotent stem cells (iPSCs) as acceptor. One of the obstacles to be addressed for translating PSC research into clinical practice is the still unsatisfactory differentiation into transplantable hematopoietic stem or mature cells. We provide an overview of the recent progresses in this field and discuss challenges and potential of iPSC-based therapies for the treatment of inherited blood disorders.

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Advances and Obstacles in Homology-Mediated Gene Editing of Hematopoietic Stem Cells

Cited by 12 publications

References 127 publications

Hematopoietic stem and progenitors cells gene editing: Beyond blood disorders

Hematopoietic stem and progenitors cells gene editing: Beyond blood disorders

Clinical genome editing to treat sickle cell disease—A brief update

Hematopoietic Cells from Pluripotent Stem Cells: Hope and Promise for the Treatment of Inherited Blood Disorders

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