In Vivo Hematopoietic Stem Cell Genome Editing: Perspectives and Limitations

Psatha, Nikoletta; Paschoudi, Kiriaki; Παπαδοπούλου, Αναστασία; Yannaki, Evangelia

doi:10.3390/genes13122222

Cited by 7 publications

(4 citation statements)

References 227 publications

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“…CRISPR epigenome editors consist of a catalytically inactivated “dead” Cas9 (dCas9) tethered to the catalytic domain of epigenetic effectors such as DNMTs or ten-eleven translocation (TET) methyl-cytosine dioxygenases, HATs, or HDACs to potentiate or repress gene expression. A gRNA complementary to the target DNA sequence navigates the CRISPR-dCas9 epi-editor to the target site, whether that is a promoter or distal cis-regulatory sequence [ 45 ]. Epigenetic editing can be used to promote (CRISPR activation, CRISPRa) or attenuate (CRISPR interference, CRISPRi), the transcriptional activity based on the recruitment of transcriptional activators (VP64) or repressors (Krüppel associated box (KRAB) domain) to specific sites [ 46 , 47 ].…”

Section: Epigenetic Modificationsmentioning

confidence: 99%

Empowering the Potential of CAR-T Cell Immunotherapies by Epigenetic Reprogramming

Alvanou

Lysandrou

Christophi

et al. 2023

Cancers

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T-cell-based, personalized immunotherapy can nowadays be considered the mainstream treatment for certain blood cancers, with a high potential for expanding indications. Chimeric antigen receptor T cells (CAR-Ts), an ex vivo genetically modified T-cell therapy product redirected to target an antigen of interest, have achieved unforeseen successes in patients with B-cell hematologic malignancies. Frequently, however, CAR-T cell therapies fail to provide durable responses while they have met with only limited success in treating solid cancers because unique, unaddressed challenges, including poor persistence, impaired trafficking to the tumor, and site penetration through a hostile microenvironment, impede their efficacy. Increasing evidence suggests that CAR-Ts’ in vivo performance is associated with T-cell intrinsic features that may be epigenetically altered or dysregulated. In this review, we focus on the impact of epigenetic regulation on T-cell differentiation, exhaustion, and tumor infiltration and discuss how epigenetic reprogramming may enhance CAR-Ts’ memory phenotype, trafficking, and fitness, contributing to the development of a new generation of potent CAR-T immunotherapies.

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Section: Epigenetic Modificationsmentioning

confidence: 99%

Empowering the Potential of CAR-T Cell Immunotherapies by Epigenetic Reprogramming

Alvanou

Lysandrou

Christophi

et al. 2023

Cancers

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“…Gene editing tools can be used to modify the CCR5 gene in hematopoietic stem cells. Initial studies have used Zinc Finger Nucleases and TALENs gene-editing tools, but have presented many limitations, such as low gene editing efficiency, high offtarget rate, and costly vector construction [24]. Despite the presence of other gene-editing techniques, CRISPR has been proven to be the most reliable and effective method [25].…”

Section: Genetic Engineering Of Hematopoietic Stem Cellsmentioning

confidence: 99%

Hematopoietic Stem Cell Transplantation As A Potential Cure For HIV-1

Scaglione,

Gallicchio

2023

JSCR

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Human Immunodeficiency Virus (HIV) is a harmful disease that destroys T lymphocytes, key cells involved in the immune system. Progression of the disease can lead to the development of Advanced Immunodeficiency Syndrome (AIDS), a chronic, life-threatening illness. For decades, antiretroviral therapy (ART) has been the standard treatment for individuals with HIV infection and has saved millions of lives. However, life-long treatment comes with unwanted consequences, and low adherence to the treatment regimen may decrease its effectiveness, causing patients to become viremic again. The only known individuals cured of HIV were treated using hematopoietic stem cell transplantations. Hematopoietic stem cells (HSC) are multipotent primitive cells that differentiate into various lineages of blood cells. Research has explored utilizing these stem cells to develop a new hematopoietic system in the host that is resistant to HIV. This review outlines the current use, progress, and challenges of allogeneic hematopoietic stem cell transplantation to cure individuals of HIV-1 infection. Current studies examine how genetic engineering tools like CRISPR/Cas9 can manipulate these stem cells to treat HIV.

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“…Single-mutation diseases such as SCD, represent ideal targets for gene editing. Moreover, the ability of gene editing to introduce targeted mutations that may cause a disease-modulatory effect made it possible to use a universal approach to target, in addition to SCD, the many different thalassemia mutations through the reactivation of the endogenous γ-globin gene [25][26][27][28][29][30][31][32]. Gene editing utilizes for the targeted introduction of point mutations or small deletions and insertions of the cells' endogenous DNA damage response mechanism.…”

Section: Introductionmentioning

confidence: 99%

Precision Editing as a Therapeutic Approach for β-Hemoglobinopathies

Paschoudi

Yannaki

Psatha

2023

IJMS

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Beta-hemoglobinopathies are the most common genetic disorders worldwide, caused by a wide spectrum of mutations in the β-globin locus, and associated with morbidity and early mortality in case of patient non-adherence to supportive treatment. Allogeneic transplantation of hematopoietic stem cells (allo-HSCT) used to be the only curative option, although the indispensable need for an HLA-matched donor markedly restricted its universal application. The evolution of gene therapy approaches made possible the ex vivo delivery of a therapeutic β- or γ- globin gene into patient-derived hematopoietic stem cells followed by the transplantation of corrected cells into myeloablated patients, having led to high rates of transfusion independence (thalassemia) or complete resolution of painful crises (sickle cell disease-SCD). Hereditary persistence of fetal hemoglobin (HPFH), a syndrome characterized by increased γ-globin levels, when co-inherited with β-thalassemia or SCD, converts hemoglobinopathies to a benign condition with mild clinical phenotype. The rapid development of precise genome editing tools (ZFN, TALENs, CRISPR/Cas9) over the last decade has allowed the targeted introduction of mutations, resulting in disease-modifying outcomes. In this context, genome editing tools have successfully been used for the introduction of HPFH-like mutations both in HBG1/HBG2 promoters or/and in the erythroid enhancer of BCL11A to increase HbF expression as an alternative curative approach for β-hemoglobinopathies. The current investigation of new HbF modulators, such as ZBTB7A, KLF-1, SOX6, and ZNF410, further expands the range of possible genome editing targets. Importantly, genome editing approaches have recently reached clinical translation in trials investigating HbF reactivation in both SCD and thalassemic patients. Showing promising outcomes, these approaches are yet to be confirmed in long-term follow-up studies.

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In Vivo Hematopoietic Stem Cell Genome Editing: Perspectives and Limitations

Cited by 7 publications

References 227 publications

Empowering the Potential of CAR-T Cell Immunotherapies by Epigenetic Reprogramming

Empowering the Potential of CAR-T Cell Immunotherapies by Epigenetic Reprogramming

Hematopoietic Stem Cell Transplantation As A Potential Cure For HIV-1

Precision Editing as a Therapeutic Approach for β-Hemoglobinopathies

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