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    BCL11A enhancer edited hematopoietic stem cells persist in rhesus monkeys without toxicity

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    Authors
    Demirci, Selami
    Zeng, Jing
    Wu, Yuxuan
    Uchida, Naoya
    Shen, Anne H.
    Pellin, Danilo
    Gamer, Jackson
    Yapundich, Morgan
    Drysdale, Claire
    Bonanno, Jasmine
    Bonifacino, Aylin C.
    Krouse, Allen
    Linde, Nathaniel Seth.
    Engels, Theresa
    Donahue, Robert E.
    Haro-Mora, Juan J.
    Leonard, Alexis
    Nassehi, Tina
    Luk, Kevin
    Porter, Shaina N.
    Lazzarotto, Cicera R.
    Tsai, Shengdar Q.
    Weiss, Mitchell
    Pruett-Miller, Shondra M.
    Wolfe, Scot A.
    Bauer, Daniel E.
    Tisdale, John F.
    Show allShow less
    UMass Chan Affiliations
    Graduate School of Biomedical Sciences
    Document Type
    Accepted Manuscript
    Publication Date
    2020-09-08
    Keywords
    Genetic diseases
    Hematology
    Hematopoietic stem cells
    Stem cell transplantation
    Transplantation
    Sickle cell disease
    β-thalassemia
    γ-globin
    CRISPR/Cas9
    gene editing
    Amino Acids, Peptides, and Proteins
    Cell Biology
    Congenital, Hereditary, and Neonatal Diseases and Abnormalities
    Genetics and Genomics
    Hematology
    Hemic and Lymphatic Diseases
    Medical Genetics
    Nucleic Acids, Nucleotides, and Nucleosides
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    Link to Full Text
    https://doi.org/10.1172/jci140189
    Abstract
    Gene editing of the erythroid-specific BCL11A enhancer in hematopoietic stem and progenitor cells (HSPCs) from sickle cell disease (SCD) patients induces fetal hemoglobin (HbF) without detectable toxicity as assessed by mouse xenotransplant. Here, we evaluated autologous engraftment and HbF induction potential of erythroid-specific BCL11A enhancer edited HSPCs in four non-human primates. We utilized a single guide RNA (sgRNA) with identical human and rhesus target sequences to disrupt a GATA1 binding site at the BCL11A +58 erythroid enhancer. Cas9 protein and sgRNA ribonucleoprotein complex (RNP) was electroporated into rhesus HSPCs, followed by autologous infusion after myeloablation. We found that gene edits persisted in peripheral blood (PB) and bone marrow (BM) for up to 101 weeks similarly for BCL11A enhancer or control locus (AAVS1) targeted cells. Biallelic BCL11A enhancer editing resulted in robust gamma-globin induction, with the highest levels observed during stress erythropoiesis. Indels were evenly distributed across PB and BM lineages. Off-target edits were not observed. Non-homologous end-joining repair alleles were enriched in engrafting HSCs. In summary, we find that edited HSCs can persist for at least 101 weeks post-transplant, and biallelic edited HSCs provide substantial HbF levels in PB red blood cells, together supporting further clinical translation of this approach.
    Source

    Demirci S, Zeng J, Wu Y, Uchida N, Shen AH, Pellin D, Gamer J, Yapundich M, Drysdale C, Bonanno J, Bonifacino AC, Krouse A, Linde NS, Engels T, Donahue RE, Haro-Mora JJ, Leonard A, Nassehi T, Luk K, Porter SN, Lazzarotto CR, Tsai SQ, Weiss M, Pruett-Miller SM, Wolfe SA, Bauer DE, Tisdale JF. BCL11A enhancer edited hematopoietic stem cells persist in rhesus monkeys without toxicity. J Clin Invest. 2020 Sep 8:140189. doi: 10.1172/JCI140189. Epub ahead of print. PMID: 32897878. Link to article on publisher's site

    DOI
    10.1172/JCI140189
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/41575
    PubMed ID
    32897878
    Related Resources

    Link to Article in PubMed

    Rights
    Copyright © 2020 American Society for Clinical Investigation. Authors' accepted manuscript posted as allowed by the publisher's self-archiving policy at https://v2.sherpa.ac.uk/id/publication/6211.
    ae974a485f413a2113503eed53cd6c53
    10.1172/JCI140189
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    Morningside Graduate School of Biomedical Sciences Scholarly Publications
    UMass Chan Faculty and Researcher Publications

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