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    PREVENTION OF MUSCULAR DYSTROPHY BY CRISPR/CPF1-MEDIATED GENE EDITING
    4.
    发明申请
    PREVENTION OF MUSCULAR DYSTROPHY BY CRISPR/CPF1-MEDIATED GENE EDITING 审中-公开

    公开(公告)号：WO2018098480A1

    公开(公告)日：2018-05-31

    申请号：PCT/US2017/063468

    申请日：2017-11-28

    申请人： THE BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM

    发明人： ZHANG, Yu ,  LONG, Chengzu ,  BASSEL-DUBY, Rhonda ,  OLSON, Eric

    IPC分类号： C12N15/10 ,  A61K48/00 ,  C07K14/47 ,  C12N15/113

    摘要： Duchenne muscular dystrophy (DMD) is an inherited X-linked disease caused by mutations in the gene encoding dystrophin, a protein required for muscle fiber integrity. The disclosure reports CRISPR/Cpfl -mediated gene editing (Myo-editing) is effective at correcting the dystrophin gene mutation in the mdx mice, a model for DMD. Further, the disclosure reports optimization of germline editing of mdx mice by engineering the permanent skipping of mutant exon and extending exon skipping to also correct the disease by post-natal delivery of adeno- associated virus (AAV). AAV-mediated Myo-editing can efficiently rescue the reading frame of dystrophin in mdx mice in vivo. The disclosure reports means of Myo-editing-mediated exon skipping has been successfully advanced from somatic tissues in mice to human DMD patients- derived iPSCs (induced pluripotent stem cells). Custom Myo-editing was performed on iPSCs from patients with differing mutations and successfully restored dystrophin protein expression for all mutations in iPSCs-derived cardiomyocytes.

    CORRECTION OF DYSTROPHIN EXON 43, EXON 45, OR EXON 52 DELETIONS IN DUCHENNE MUSCULAR DYSTROPHY
    6.
    发明申请
    CORRECTION OF DYSTROPHIN EXON 43, EXON 45, OR EXON 52 DELETIONS IN DUCHENNE MUSCULAR DYSTROPHY 审中-公开

    公开(公告)号：WO2019246480A1

    公开(公告)日：2019-12-26

    申请号：PCT/US2019/038398

    申请日：2019-06-21

    申请人： THE BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM

    发明人： MIN, Yi-Li ,  BASSEL-DUBY, Rhonda ,  OLSON, Eric

    IPC分类号： C12N15/11 ,  C12N15/113

    摘要： Duchenne muscular dystrophy (DMD), which affects 1 in 5,000 male births, is one of the most common genetic disorders of children. This disease is caused by an absence or deficiency of dystrophin protein in striated muscle. The major DMD deletion "hot spots" are found between exon 6 to 8, and exons 45 to 53. Here, three DMD mouse models are provided that can be used to test a variety of DMD exon skipping and refraining strategies. Among these are, CRISPR/Cas9 oligonucleotides, small molecules or other therapeutic modalities that promote exon skipping or exon refraining or micro dystrophin mini genes or cell based therapies. Methods for restoring the reading frame of exon 43, exon 45, and exon 52 deletion via CRISPR-mediated exon skipping and reframing in the humanized DMD mouse model, in patient-derived iPSCs and ultimately, in patients using various delivery systems are also contemplated. The impact of CRISPR technology on DMD is that gene editing can permanently correct mutations.

    PREVENTION OF MUSCULAR DYSTROPHY BY CRISPR/CAS9-MEDIATED GENE EDITING
    7.
    发明申请
    PREVENTION OF MUSCULAR DYSTROPHY BY CRISPR/CAS9-MEDIATED GENE EDITING 审中-公开
    通过CRISPR / CAS9介导的基因编辑预防肌瘤

    公开(公告)号：WO2016025469A1

    公开(公告)日：2016-02-18

    申请号：PCT/US2015/044639

    申请日：2015-08-11

    申请人： THE BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM

    发明人： OLSON, Eric, N. ,  LONG, Chengzu ,  MCANALLY, John, R. ,  SHELTON, John, M. ,  BASSEL-DUBY, Rhonda

    IPC分类号： A61K48/00 ,  C12N15/00 ,  C12N5/00

    CPC分类号： A61K48/0058 ,  A61K38/465 ,  A61P21/00 ,  C12N15/113 ,  C12N2310/20 ,  C12N2750/14143 ,  C12Y301/00

    摘要： Duchenne muscular dystrophy (DMD) is an inherited X-linked disease caused by mutations in the gene encoding dystrophin, a protein required for muscle fiber integrity. The disclosure reports CRISPR/Cas9-mediated gene editing (Myo-editing) is effective at correcting the dystrophin gene mutation in the mdx mice, a model for DMD. Further, the disclosure reports optimization of germline editing of mdx mice by engineering the permanent skipping of mutant exon (exon 23) and extending exon skipping to also correct the disease by post-natal delivery of adeno-associate virus (AAV). AAV-mediated Myo-editing can efficiently rescue the reading frame of dystrophin in mdx mice in vivo. The disclosure reports means of Myo-editing-mediated exon skipping has been successfully advanced from somatic tissues in mice to human DMD patients-derived iPSCs (induced pluripotent stem cells). Custom Myo-editing was performed on iPSCs from patients with differing mutations and successfully restored dystrophin protein expression for all mutations in iPSCs-derived cardiomyocytes.

    摘要翻译： 杜氏肌营养不良（DMD）是由编码肌营养不良蛋白的基因（肌纤维完整性所需的蛋白质）的突变引起的遗传性X连锁疾病。 披露报告CRISPR / Cas9介导的基因编辑（Myo-editing）在校正mdx小鼠中的肌营养不良蛋白基因突变中是有效的，DMD的模型。 此外，该公开报告通过工程化突变外显子（外显子23）的永久性跳过并延伸外显子跳过以通过产后输送腺相关病毒（AAV）来纠正疾病来优化mdx小鼠的种系编辑。 AAV介导的Myo编辑可以有效地挽救体内mdx小鼠肌营养不良蛋白的阅读框架。 Myo编辑介导的外显子跳跃的披露报告手段已经从小鼠的体细胞组织中成功推进到人DMD患者来源的iPSC（诱导多能干细胞）。 在具有不同突变的患者的iPSC上进行定制Myo编辑，并成功地恢复了iPSC来源的心肌细胞中所有突变的肌营养不良蛋白表达。

    DMD REPORTER MODELS CONTAINING HUMANIZED DUSCHENE MUSCULAR DYSTROPHY MUTATIONS
    10.
    发明申请
    DMD REPORTER MODELS CONTAINING HUMANIZED DUSCHENE MUSCULAR DYSTROPHY MUTATIONS 审中-公开

    公开(公告)号：WO2018107003A1

    公开(公告)日：2018-06-14

    申请号：PCT/US2017/065268

    申请日：2017-12-08

    申请人： THE BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM

    发明人： AMOASII, Leonela ,  LONG, Chengzu ,  BASSEL-DUBY, Rhonda ,  OLSON, Eric

    IPC分类号： C12N9/22 ,  C12N15/10 ,  C12N15/11 ,  C12N15/90

    摘要： CRISPR/Cas9-mediated genome editing holds clinical potential for treating genetic diseases, such as Duchenne muscular dystrophy (DMD), which is caused by mutations in the dystrophin gene. In vivo AAV-mediated delivery of gene-editing components machinery has been shown to successfully remove mutant sequence to generate an exon skipping in the cardiac and skeletal muscle cells of postnatal mdx mice, a model of DMD. Using different modes of AAV9 delivery, the restoration of dystrophin protein expression in cardiac and skeletal muscle of mdx mice was achieved. Here, a humanized mouse model for DMD is created to help test the efficacy of genome editing to cure DMD. Additionally, to facilitate the analysis of exon skipping strategies in vivo in a non-invasive way, a reporter luciferase knock-in version of the mouse model was prepared. These humanized mouse models provide the ability to study correcting of mutations responsible for DMD in vivo .