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  1. Article ; Online: Hematopoietic Stem Cell Gene-Addition/Editing Therapy in Sickle Cell Disease.

    Germino-Watnick, Paula / Hinds, Malikiya / Le, Anh / Chu, Rebecca / Liu, Xiong / Uchida, Naoya

    Cells

    2022  Volume 11, Issue 11

    Abstract: Autologous hematopoietic stem cell (HSC)-targeted gene therapy provides a one-time cure for various genetic diseases including sickle cell disease (SCD) and β-thalassemia. SCD is caused by a point mutation (20A > T) in the β-globin gene. Since SCD is the ...

    Abstract Autologous hematopoietic stem cell (HSC)-targeted gene therapy provides a one-time cure for various genetic diseases including sickle cell disease (SCD) and β-thalassemia. SCD is caused by a point mutation (20A > T) in the β-globin gene. Since SCD is the most common single-gene disorder, curing SCD is a primary goal in HSC gene therapy. β-thalassemia results from either the absence or the reduction of β-globin expression, and it can be cured using similar strategies. In HSC gene-addition therapy, patient CD34+ HSCs are genetically modified by adding a therapeutic β-globin gene with lentiviral transduction, followed by autologous transplantation. Alternatively, novel gene-editing therapies allow for the correction of the mutated β-globin gene, instead of addition. Furthermore, these diseases can be cured by γ-globin induction based on gene addition/editing in HSCs. In this review, we discuss HSC-targeted gene therapy in SCD with gene addition as well as gene editing.
    MeSH term(s) Anemia, Sickle Cell/genetics ; Anemia, Sickle Cell/metabolism ; Anemia, Sickle Cell/therapy ; Gene Editing/methods ; Genetic Therapy/methods ; Hematopoietic Stem Cell Transplantation/methods ; Hematopoietic Stem Cells/metabolism ; Humans ; beta-Globins/genetics ; beta-Thalassemia/genetics ; beta-Thalassemia/metabolism ; beta-Thalassemia/therapy
    Chemical Substances beta-Globins
    Language English
    Publishing date 2022-06-04
    Publishing country Switzerland
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells11111843
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Advances in CRISPR Delivery Methods: Perspectives and Challenges.

    Demirci, Selami / Essawi, Khaled / Germino-Watnick, Paula / Liu, Xiong / Hakami, Waleed / Tisdale, John F

    The CRISPR journal

    2022  Volume 5, Issue 5, Page(s) 660–676

    Abstract: With the advent of new genome editing technologies and the emphasis placed on their optimization, the genetic and phenotypic correction of a plethora of diseases sit on the horizon. Ideally, genome editing approaches would provide long-term solutions ... ...

    Abstract With the advent of new genome editing technologies and the emphasis placed on their optimization, the genetic and phenotypic correction of a plethora of diseases sit on the horizon. Ideally, genome editing approaches would provide long-term solutions through permanent disease correction instead of simply treating patients symptomatically. Although various editing machinery options exist, the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas (CRISPR-associated protein) editing technique has emerged as the most popular due to its high editing efficiency, simplicity, and affordability. However, while CRISPR technology is gradually being perfected, optimization is futile without accessible, effective, and safe delivery to the desired cell or tissue. Therefore, it is important that scientists simultaneously focus on inventing and improving delivery modalities for editing machinery as well. In this review, we will discuss the critical details of viral and nonviral delivery systems, including payload, immunogenicity, efficacy in delivery, clinical application, and future directions.
    MeSH term(s) Humans ; Gene Editing/methods ; CRISPR-Cas Systems/genetics ; CRISPR-Associated Proteins/genetics
    Chemical Substances CRISPR-Associated Proteins
    Language English
    Publishing date 2022-10-19
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 3017891-5
    ISSN 2573-1602 ; 2573-1599
    ISSN (online) 2573-1602
    ISSN 2573-1599
    DOI 10.1089/crispr.2022.0051
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Fertility-preserving myeloablative conditioning using single-dose CD117 antibody-drug conjugate in a rhesus gene therapy model.

    Uchida, Naoya / Stasula, Ulana / Demirci, Selami / Germino-Watnick, Paula / Hinds, Malikiya / Le, Anh / Chu, Rebecca / Berg, Alexander / Liu, Xiong / Su, Ling / Wu, Xiaolin / Krouse, Allen E / Linde, N Seth / Bonifacino, Aylin / Hong, So Gun / Dunbar, Cynthia E / Lanieri, Leanne / Bhat, Anjali / Palchaudhuri, Rahul /
    Bennet, Bindu / Hoban, Megan / Bertelsen, Kirk / Olson, Lisa M / Donahue, Robert E / Tisdale, John F

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 6291

    Abstract: Hematopoietic stem cell (HSC) gene therapy has curative potential; however, its use is limited by the morbidity and mortality associated with current chemotherapy-based conditioning. Targeted conditioning using antibody-drug conjugates (ADC) holds ... ...

    Abstract Hematopoietic stem cell (HSC) gene therapy has curative potential; however, its use is limited by the morbidity and mortality associated with current chemotherapy-based conditioning. Targeted conditioning using antibody-drug conjugates (ADC) holds promise for reduced toxicity in HSC gene therapy. Here we test the ability of an antibody-drug conjugate targeting CD117 (CD117-ADC) to enable engraftment in a non-human primate lentiviral gene therapy model of hemoglobinopathies. Following single-dose CD117-ADC, a >99% depletion of bone marrow CD34 + CD90 + CD45RA- cells without lymphocyte reduction is observed, which results are not inferior to multi-day myeloablative busulfan conditioning. CD117-ADC, similarly to busulfan, allows efficient engraftment, gene marking, and vector-derived fetal hemoglobin induction. Importantly, ADC treatment is associated with minimal toxicity, and CD117-ADC-conditioned animals maintain fertility. In contrast, busulfan treatment commonly causes severe toxicities and infertility in humans. Thus, the myeloablative capacity of single-dose CD117-ADC is sufficient for efficient engraftment of gene-modified HSCs while preserving fertility and reducing adverse effects related to toxicity in non-human primates. This targeted conditioning approach thus provides the proof-of-principle to improve risk-benefit ratio in a variety of HSC-based gene therapy products in humans.
    MeSH term(s) Animals ; Busulfan/pharmacology ; Genetic Therapy/methods ; Hematopoietic Stem Cell Transplantation/methods ; Hematopoietic Stem Cells ; Immunoconjugates/pharmacology ; Proto-Oncogene Proteins c-kit/immunology ; Proto-Oncogene Proteins c-kit/therapeutic use ; Macaca mulatta/immunology
    Chemical Substances Busulfan (G1LN9045DK) ; Immunoconjugates ; Proto-Oncogene Proteins c-kit (EC 2.7.10.1)
    Language English
    Publishing date 2023-10-12
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-41153-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Forced enhancer-promoter rewiring to alter gene expression in animal models.

    Peslak, Scott A / Demirci, Selami / Chandra, Vemika / Ryu, Byoung / Bhardwaj, Saurabh K / Jiang, Jing / Rupon, Jeremy W / Throm, Robert E / Uchida, Naoya / Leonard, Alexis / Essawi, Khaled / Bonifacino, Aylin C / Krouse, Allen E / Linde, Nathaniel S / Donahue, Robert E / Ferrara, Francesca / Wielgosz, Matthew / Abdulmalik, Osheiza / Hamagami, Nicole /
    Germino-Watnick, Paula / Le, Anh / Chu, Rebecca / Hinds, Malikiya / Weiss, Mitchell J / Tong, Wei / Tisdale, John F / Blobel, Gerd A

    Molecular therapy. Nucleic acids

    2023  Volume 31, Page(s) 452–465

    Abstract: Transcriptional enhancers can be in physical proximity of their target genes via chromatin looping. The enhancer at the β-globin locus (locus control region [LCR]) contacts the fetal-type ( ...

    Abstract Transcriptional enhancers can be in physical proximity of their target genes via chromatin looping. The enhancer at the β-globin locus (locus control region [LCR]) contacts the fetal-type (
    Language English
    Publishing date 2023-01-31
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2662631-7
    ISSN 2162-2531
    ISSN 2162-2531
    DOI 10.1016/j.omtn.2023.01.016
    Database MEDical Literature Analysis and Retrieval System OnLINE

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