Megakaryocytic particles and microparticles for in vivo hematopoietic cell and gene therapies

    公开(公告)号:US11820968B2

    公开(公告)日:2023-11-21

    申请号:US16711396

    申请日:2019-12-11

    IPC分类号: A61K35/19 C12N5/078 A01N1/02

    摘要: Applications in transfusion medicine requiring platelets, and hematopoietic stem-cell transplantations require either platelets or enhancement of in vivo platelet biogenesis. Gene therapy applications of hematopoietic stem and progenitor cells (HSPCs) require effective and specific modification of HSPCs by DNA, RNA or other biological molecules. Here we disclose methods for the generation, and modification of megakaryocytic microparticles (MkMPs), proplatelets, preplatelets, platelet-like particles and megakaryocyte extracellular vesicles, that can be used in the aforementioned transfusion and transplantation medicine applications and in gene therapy applications involving hematopoietic stem cells. The biological effects of modified or unmodified MkMPs have never been previously disclosed and thus, this invention claims all biological applications of MkMPs in in vivo therapeutic applications to produce various cells and cell parts, modify various target cells or deliver molecules including drugs to HSPCs and related cells.

    MICRORNAS ENRICHED IN MEGAKARYOCYTIC EXTRACELLULAR VESICLES AND USES THEREOF

    公开(公告)号:US20220372441A1

    公开(公告)日:2022-11-24

    申请号:US17770433

    申请日:2020-10-21

    IPC分类号: C12N5/078 C12N15/113

    摘要: The present invention relates to a method for inducing megakaryocytic differentiation of hematopoietic stem/progenitor cells (HSPCs). The method comprises transferring into the HSPCs an effective amount of small RNAs. The HSPCs may differentiate into megakaryocytes in the absence of thrombopoietin (TPO) and/or without using megakaryocytic microparticles (MkMPs). The small RNAs may be micro RNAs (miRs) selected from the group consisting of miR-486, miR-22, miR-191, miR-181, miR-378, miR-26, let-7, miR-92, miR-126, miR-92, miR-21, miR-146, miR-181, and combinations thereof. For example, the small RNAs are miR-486 and miR-22. The small RNAs may be synthetic or isolated from cells. Also provided is a method for enhancing megakaryocytic differentiation of HSPCs cultured with megakaryocytic microparticles MkMPs in the presence of an effective amount of one or more exogenous small RNAs (e.g., miR-486).

    Megakaryocytic particles and microparticles for cell therapy & fate modification of stem and progenitor cells
    3.
    发明申请
    Megakaryocytic particles and microparticles for cell therapy & fate modification of stem and progenitor cells 审中-公开
    用于细胞治疗的巨核细胞颗粒和微粒以及干细胞和祖细胞的命运修饰

    公开(公告)号:US20170058262A1

    公开(公告)日:2017-03-02

    申请号:US15308221

    申请日:2015-05-18

    IPC分类号: C12N5/078 A61K35/19

    摘要: Applications in transfusion medicine requiring platelets, and hematopoietic stem-cell transplantations require either platelets or enhancement of in vivo platelet biogenesis. Gene therapy applications of hematopoietic stem and progenitor cells (HSPCs) require effective and specific modification of HSPCs by DNA, RNA or other biological molecules. Here we disclose methods for the generation, and modification of megakaryocytic microparticles (MkMPs) or microvesicles, that can be used in the aforementioned transfusion and transplantation medicine applications and in gene therapy applications involving hematopoietic stem cells. The biological effects of modified or unmodified MkMPs have never been previously disclosed and thus, this invention claims all biological applications of MkMPs in in vivo therapeutic applications or ex vivo applications to produce various cells and cell parts, modify various target cells or deliver molecules including drugs to HSPCs and related cells.

    摘要翻译: 在需要血小板的输血药物和造血干细胞移植中的应用需要血小板或增强体内血小板生物发生。 造血干细胞和祖细胞(HSPC)的基因治疗应用需要通过DNA,RNA或其他生物分子对HSPC进行有效和特异性的修饰。 在这里,我们公开了可用于上述输血和移植医学应用以及涉及造血干细胞的基因治疗应用中的巨核细胞微粒(MkMP)或微泡的产生和修饰的方法。 修饰或未经修饰的MkMPs的生物学效应从未在之前公开过,因此,本发明要求所有生物学应用MkMPs在体内治疗应用或离体应用中产生各种细胞和细胞部分,修饰各种靶细胞或递送分子包括药物 到HSPC和相关细胞。

    Megakaryocytic particles and microparticles for cell therapy and fate modification of stem and progenitor cells

    公开(公告)号:US10538738B2

    公开(公告)日:2020-01-21

    申请号:US15308221

    申请日:2015-05-18

    IPC分类号: C12N5/078 A61K35/19

    摘要: Applications in transfusion medicine requiring platelets, and hematopoietic stem-cell transplantations require either platelets or enhancement of in vivo platelet biogenesis. Gene therapy applications of hematopoietic stem and progenitor cells (HSPCs) require effective and specific modification of HSPCs by DNA, RNA or other biological molecules. Here we disclose methods for the generation, and modification of megakaryocytic microparticles (MkMPs) or microvesicles, that can be used in the aforementioned transfusion and transplantation medicine applications and in gene therapy applications involving hematopoietic stem cells. The biological effects of modified or unmodified MkMPs have never been previously disclosed and thus, this invention claims all biological applications of MkMPs in in vivo therapeutic applications or ex vivo applications to produce various cells and cell parts, modify various target cells or deliver molecules including drugs to HSPCs and related cells.

    REVERSE ENGINEERING GENOME-SCALE METABOLIC NETWORK RECONSTRUCTIONS FOR ORGANISMS WITH INCOMPLETE GENOME ANNOTATION AND DEVELOPING CONSTRAINTS USING PROTON FLUX STATES AND NUMERICALLY-DETERMINED SUB-SYSTEMS
    5.
    发明申请
    REVERSE ENGINEERING GENOME-SCALE METABOLIC NETWORK RECONSTRUCTIONS FOR ORGANISMS WITH INCOMPLETE GENOME ANNOTATION AND DEVELOPING CONSTRAINTS USING PROTON FLUX STATES AND NUMERICALLY-DETERMINED SUB-SYSTEMS 失效
    反向工程基因代数网络重建用于使用原子通量状态和数字确定子系统的不完全基因组调整和发展约束的机构

    公开(公告)号:US20090259451A1

    公开(公告)日:2009-10-15

    申请号:US12422772

    申请日:2009-04-13

    IPC分类号: G06G7/58 G06F17/30 G06F19/00

    CPC分类号: G06F19/12

    摘要: A genome-scale metabolic network reconstruction for Clostridium acetobutylicum (ATCC 824) was created using a new semi-automated reverse engineering algorithm. This invention includes algorithms and software that can reconstruct genome-scale metabolic networks for cell-types available through the Kyoto Encyclopedia of Genes and Genomes. This method can also be used to complete partial metabolic networks and cell signaling networks where adequate starting information base is available. The software may use a semi-automated approach which uses a priori knowledge of the cell-type from the user. Upon completion, the program output is a genome-scale stoichiometric matrix capable of cell growth in silico. The invention also includes methods for developing flux constraints and reducing the number of possible solutions to an under-determined system by applying specific proton flux states and identifying numerically-determined sub-systems. Although the model-building and analysis tools described in this invention were initially applied to C. acetobutylicum, the novel algorithms and software can be applied universally.

    摘要翻译: 使用新的半自动逆向工程算法创建丙酮丁醇梭菌(ATCC 824)的基因组大小代谢网络重建。 本发明包括可重建通过“京都百科全书基因组”获得的细胞类型的基因组大规模代谢网络的算法和软件。 该方法也可用于完成部分代谢网络和小区信令网络,其中有足够的启动信息库可用。 软件可以使用半自动化方法,其使用来自用户的小区类型的先验知识。 完成后,程序输出是能够在硅胶中生长细胞的基因组大小的化学计量矩阵。 本发明还包括通过应用特定质子通量状态和识别数字确定的子系统来形成通量约束并减少对未确定系统的可能解决方案的数量的方法。 虽然本发明中描述的模型构建和分析工具最初被应用于丙酮丁醇梭菌,但是新颖的算法和软件可以普遍应用。

    Reverse engineering genome-scale metabolic network reconstructions for organisms with incomplete genome annotation and developing constraints using proton flux states and numerically-determined sub-systems
    8.
    发明授权
    Reverse engineering genome-scale metabolic network reconstructions for organisms with incomplete genome annotation and developing constraints using proton flux states and numerically-determined sub-systems 失效
    逆向工程基因组大规模代谢网络重建的生物与不完整的基因组注释和发展约束使用质子通量状态和数字确定子系统

    公开(公告)号:US08311790B2

    公开(公告)日:2012-11-13

    申请号:US12422772

    申请日:2009-04-13

    IPC分类号: G06F19/12

    CPC分类号: G06F19/12

    摘要: A genome-scale metabolic network reconstruction for Clostridium acetobutylicum (ATCC 824) was created using a new semi-automated reverse engineering algorithm. This invention includes algorithms and software that can reconstruct genome-scale metabolic networks for cell-types available through the Kyoto Encyclopedia of Genes and Genomes. This method can also be used to complete partial metabolic networks and cell signaling networks where adequate starting information base is available. The software may use a semi-automated approach which uses a priori knowledge of the cell-type from the user. Upon completion, the program output is a genome-scale stoichiometric matrix capable of cell growth in silico. The invention also includes methods for developing flux constraints and reducing the number of possible solutions to an under-determined system by applying specific proton flux states and identifying numerically-determined sub-systems. Although the model-building and analysis tools described in this invention were initially applied to C. acetobutylicum, the novel algorithms and software can be applied universally.

    摘要翻译: 使用新的半自动逆向工程算法创建丙酮丁醇梭菌(ATCC 824)的基因组大小代谢网络重建。 本发明包括可重建通过“京都百科全书基因组”获得的细胞类型的基因组大规模代谢网络的算法和软件。 该方法也可用于完成部分代谢网络和小区信令网络,其中有足够的启动信息库可用。 软件可以使用半自动化方法,其使用来自用户的小区类型的先验知识。 完成后,程序输出是能够在硅胶中生长细胞的基因组大小的化学计量矩阵。 本发明还包括通过应用特定质子通量状态和识别数字确定的子系统来形成通量约束并减少对未确定系统的可能解决方案的数量的方法。 虽然本发明中描述的模型构建和分析工具最初被应用于丙酮丁醇梭菌,但是新颖的算法和软件可以普遍应用。