Therapeutic base editing of human hematopoietic stem cells

Zeng, Jing; Wu, Yuxuan; Ren, Chunyan; Bonanno, Jasmine; Shen, Anne H.; Shea, Devlin; Gehrke, Jason; Clement, Kendell; Luk, Kevin; Yao, Qiuming; Kim, Rachel; Wolfe, Scot A.; Manis, John P.; Pinello, Luca; Joung, J. Keith; Bauer, Daniel E.

doi:10.1038/s41591-020-0790-y

Cited by 226 publications

(175 citation statements)

References 33 publications

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“…This is true even with very different modalities of Cas9 (mRNA, recombinant protein), guide RNA (synthetic, adeno-associated virus (AAV) expressed), and HDR donor (single-stranded DNA, AAV6) ( Dever et al., 2016 ; DeWitt et al., 2016 ; Genovese et al., 2014b ; Hoban et al., 2015 ; Kim et al., 2014 ; Wang et al., 2015 ). A recent report also found that a specific subtype of base editing by nucleotide deaminases at the BCL11A erythroid enhancer is less efficient in quiescent human HSCs than in non-quiescent progenitor cells ( Zeng et al., 2020 ). Our results indicate that the observed in vivo lack of HDR is not caused by an inability to target immunophenotypic LT-HSCs, nor toxicity caused by the act of performing HDR itself ( Ihry et al., 2018 ), but is instead because the repopulating HSCs are in an inappropriate phase of the cell cycle to perform HDR.…”

Section: Discussionmentioning

confidence: 99%

Controlled Cycling and Quiescence Enables Efficient HDR in Engraftment-Enriched Adult Hematopoietic Stem and Progenitor Cells

et al. 2020

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Section: Discussionmentioning

confidence: 99%

Controlled Cycling and Quiescence Enables Efficient HDR in Engraftment-Enriched Adult Hematopoietic Stem and Progenitor Cells

et al. 2020

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“…SaKKH-BE3, a BE with SaCas9-KKH locator, was used to treat phenylketonuria in adult mice through the delivery of adeno-associated virus [89]. Recently, A3A (N57Q)-BE3 was used to edit the enhancer region of B cell lymphoma/leukemia 11A (BCL11A) gene and expression of fetal hemoglobin (HbF) was induced successfully, which showed therapeutic benefits for sickle cell disease and β-thalassemia [90]. In addition to animals, Zong et al successfully applied codon-optimized BE3 [plant base editor (PBE)] in plants [61] and later, the same lab also optimized hA3A-BE3 to develop the plant version of A3A-PBE to achieve higher editing efficiencies in plants [64].…”

Section: Applications Of Bes and Pesmentioning

confidence: 99%

A Tale of Two Moieties: Rapidly Evolving CRISPR/Cas-Based Genome Editing

Yang

Chen

2020

Trends in Biochemical Sciences

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Highlights CRISPR/Cas with different modules for independent target binding and cleavage has evolved to achieve convenient and precise genome editing. The endonuclease effector in conventional CRISPR/Cas genome editing systems can be replaced by nucleobase deaminases and the resulting base editors (BEs) enable single base changes. By fusing CRISPR/Cas with reverse transcriptases, prime editors (PEs) represent a new way to accomplish genetic changes, including all types of base substitutions, small indels, and their combinations. Both BEs and PEs are of potential in correcting disease-associated mutations. Genome-wide and/or transcriptomewide off-target mutations are catalyzed by the nucleobase deaminase effector in BEs, which are independent of the fused gRNA/Cas moiety.

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“…Base editing approaches by nucleotide deaminases linked to synthesized CRISPR guides to target the erythroid enhancer region of BCL11A are also in early stages of development 57 …”

Section: Methodsmentioning

confidence: 99%

Gene therapies for transfusion dependent β‐thalassemia: Current status and critical criteria for success

Soni

2020

American J Hematol

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Thalassemia is one of the most prevalent monogenic diseases usually caused by quantitative defects in the production of β‐globin leading to severe anemia. Technological advances in genome sequencing, stem cell selection, viral vector development, transduction and gene editing strategies now allow for efficient ex‐vivo genetic manipulation of human stem cells that can lead to production of hemoglobin, leading to a meaningful clinical benefit in thalassemia patients. In this review, the status of the gene‐therapy approaches available for transfusion dependent thalassemia are discussed, along with the critical criteria that affect efficacy and lessons that have been learned from the early phase clinical trials. Salient steps necessary for the clinical development, manufacturing, and regulatory approvals of gene therapies for thalassemia are also highlighted, so that the potential of these therapies can be realized. It is highly anticipated that gene therapies will soon become a treatment option for patients lacking compatible donors for hematopoietic stem cell transplant and will offer an alternative for definitive treatment of β‐thalassemia.

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Therapeutic base editing of human hematopoietic stem cells

Cited by 226 publications

References 33 publications

Controlled Cycling and Quiescence Enables Efficient HDR in Engraftment-Enriched Adult Hematopoietic Stem and Progenitor Cells

Controlled Cycling and Quiescence Enables Efficient HDR in Engraftment-Enriched Adult Hematopoietic Stem and Progenitor Cells

A Tale of Two Moieties: Rapidly Evolving CRISPR/Cas-Based Genome Editing

Gene therapies for transfusion dependent β‐thalassemia: Current status and critical criteria for success

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