Ex Vivo Nanoparticle Drug Delivery Targeted to Human Renal Allograft Endothelium

针对人肾同种异体移植物内皮的体外纳米颗粒药物输送

基本信息

  • 批准号:
    10197784
  • 负责人:
  • 金额:
    $ 48.94万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-07-01 至 2023-06-30
  • 项目状态:
    已结题

项目摘要

A significant proportion of patients with renal failure who would benefit from kidney transplantation are highly pre-sensitized, i.e. they have high titers of pre-formed circulating antibodies (Abs) reactive with 80% or more of non-self allelic forms of class I and/or class II HLA antigens called panel reactive Abs (PRA). Upon transplantation, host PRA will bind to graft HLA antigens that are highly expressed on graft endothelial cells (ECs) where they activate host human complement resulting in deposition of membrane attack complex (MAC) on the ECs. Human MAC does not lyse human ECs, but instead alters them to express gene products that promote inflammation. The inflammatory milieu favors activation of adaptive immune effectors at the expense of protective immunoregulation. Consequently, if transplanted, patients with high titer PRA have increased episodes of acute and chronic rejection resulting in more graft failure and graft loss. Current therapeutic approaches include plasmapheresis to reduce the titer of circulating PRA, targeted elimination of Ab-producing cells and/or administration of high doses of intravenous gamma globulin to reduce inflammation, but PRA titers return and these interventions have had only limited impact on outcomes. We propose a novel strategy to complement these approaches, namely to reduce the response of graft ECs to PRA/MAC by reducing expression of HLA antigen targets and/or by inhibiting PRA/MAC signaling in ECs. The latter approach is based upon our elucidation of the relevant signaling pathways. To accomplish this, we will develop safe, polymeric nanoparticles (NPs) that are targeted towards graft ECs by means of conjugated anti-EC Abs and use these NPs to deliver siRNAs or small molecule therapeutics (“drugs”) during a period of ex vivo normothermic perfusion (EVNP), an approach that is being applied to improve energy stores in kidneys and other organs from deceased donors prior to transplantation. The NPs, which will be bound to and internalized by the graft ECs, will then serve as a depot for sustained release of the therapeutic agent for a period sufficient to allow graft accommodation and/or host immunoregulation to develop. In Specific Aim 1, we will use human EC cultures and human artery segments interposed into the aortae of immunodeficient mice to identify the optimal siRNAs or drugs that can protect ECs from PRA. Our initial target will be prevention of Akt activation, a key step in PRA/MAC signaling. In Specific Aim 2, we will identify optimal Abs for targeting renal human ECs and use these to identify conditions for efficient pan-EC delivery in human kidneys unsuitable for clinical transplantation that are subjected to EVNP by our collaborators at the University of Cambridge. (U01 support will be used only for experiments and analyses conducted at Yale; the costs of experimental EVNP will be provided by our Cambridge colleagues who are supported by a grant from the UK National Institute for Health Research and experimental EVNP will be conducted at the University of Cambridge under their Ethics Approval.) If successful, this approach can be extended to other uses and could justify a human clinical trial.
肾移植对肾功能衰竭患者有很大的益处

项目成果

期刊论文数量(12)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Coronavirus Disease 2019 (COVID-19) Coronary Vascular Thrombosis: Correlation with Neutrophil but Not Endothelial Activation.
  • DOI:
    10.1016/j.ajpath.2021.09.004
  • 发表时间:
    2022-01
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Johnson JE;McGuone D;Xu ML;Jane-Wit D;Mitchell RN;Libby P;Pober JS
  • 通讯作者:
    Pober JS
Nucleic Acid Delivery to the Vascular Endothelium.
  • DOI:
    10.1021/acs.molpharmaceut.2c00653
  • 发表时间:
    2022-12-05
  • 期刊:
  • 影响因子:
    4.9
  • 作者:
    Reschke, Melanie;Piotrowski-Daspit, Alexandra S.;Pober, Jordan S.;Saltzman, W. Mark
  • 通讯作者:
    Saltzman, W. Mark
Metabolic reprogramming by immune-responsive gene 1 up-regulation improves donor heart preservation and function.
  • DOI:
    10.1126/scitranslmed.ade3782
  • 发表时间:
    2023-02-08
  • 期刊:
  • 影响因子:
    17.1
  • 作者:
    Lei, Ienglam;Huang, Wei;Noly, Pierre Emmanuel;Naik, Suyash;Ghali, Miriyam;Liu, Liu;Pagani, Francis D.;Abou El Ela, Ashraf;Pober, Jordan S.;Pitt, Bertram;Platt, Jeffrey L.;Cascalho, Marilia;Wang, Zhong;Chen, Y. Eugene;Mortensen, Richard M.;Tang, Paul C.
  • 通讯作者:
    Tang, Paul C.
Ex vivo pretreatment of human vessels with siRNA nanoparticles provides protein silencing in endothelial cells.
  • DOI:
    10.1038/s41467-017-00297-x
  • 发表时间:
    2017-08-04
  • 期刊:
  • 影响因子:
    16.6
  • 作者:
    Cui J;Qin L;Zhang J;Abrahimi P;Li H;Li G;Tietjen GT;Tellides G;Pober JS;Mark Saltzman W
  • 通讯作者:
    Mark Saltzman W
Nanoparticle targeting to the endothelium during normothermic machine perfusion of human kidneys.
  • DOI:
    10.1126/scitranslmed.aam6764
  • 发表时间:
    2017-11-29
  • 期刊:
  • 影响因子:
    17.1
  • 作者:
    Tietjen GT;Hosgood SA;DiRito J;Cui J;Deep D;Song E;Kraehling JR;Piotrowski-Daspit AS;Kirkiles-Smith NC;Al-Lamki R;Thiru S;Bradley JA;Saeb-Parsy K;Bradley JR;Nicholson ML;Saltzman WM;Pober JS
  • 通讯作者:
    Pober JS
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JORDAN S POBER其他文献

JORDAN S POBER的其他文献

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{{ truncateString('JORDAN S POBER', 18)}}的其他基金

Ex Vivo Nanoparticle Drug Delivery Targeted to Human Allograft Endothelium
针对人同种异体移植物内皮的体外纳米颗粒药物输送
  • 批准号:
    10783379
  • 财政年份:
    2023
  • 资助金额:
    $ 48.94万
  • 项目类别:
Assessment of immunogenicity and antigenicity of different human cell types in natural and 3D-printed allografts
评估天然和 3D 打印同种异体移植物中不同人类细胞类型的免疫原性和抗原性
  • 批准号:
    10353416
  • 财政年份:
    2021
  • 资助金额:
    $ 48.94万
  • 项目类别:
Assessment of immunogenicity and antigenicity of different human cell types in natural and 3D-printed allografts
评估天然和 3D 打印同种异体移植物中不同人类细胞类型的免疫原性和抗原性
  • 批准号:
    10194232
  • 财政年份:
    2021
  • 资助金额:
    $ 48.94万
  • 项目类别:
Ex Vivo Nanoparticle Drug Delivery Targeted to Human Renal Allograft Endothelium
针对人肾同种异体移植物内皮的体外纳米颗粒药物输送
  • 批准号:
    10155842
  • 财政年份:
    2017
  • 资助金额:
    $ 48.94万
  • 项目类别:
Optimizing Therapeutic Revascularization by Endothelial Cell Transplantation
通过内皮细胞移植优化治疗性血运重建
  • 批准号:
    9516109
  • 财政年份:
    2017
  • 资助金额:
    $ 48.94万
  • 项目类别:
Targeting Nanoparticles for Drug Delivery to Renal Graft Endothelium during Ex Vivo Normothermic Perfusion
体外常温灌注期间靶向纳米颗粒将药物递送至肾移植物内皮
  • 批准号:
    9164300
  • 财政年份:
    2016
  • 资助金额:
    $ 48.94万
  • 项目类别:
Bioengineered siRNA/Nanoparticles to Prevent Human Transplant Rejection
生物工程 siRNA/纳米颗粒可防止人体移植排斥
  • 批准号:
    8693080
  • 财政年份:
    2013
  • 资助金额:
    $ 48.94万
  • 项目类别:
Spatiotemporal Delivery of miRNA Anatgomir for Promoting Vascular Self-Assembly
miRNA Anatgomir 的时空传递促进血管自组装
  • 批准号:
    8322816
  • 财政年份:
    2011
  • 资助金额:
    $ 48.94万
  • 项目类别:
Controlled Spatiotemporal Delivery of miRNA Anatgomir for Promoting Vascular Self
受控时空递送 miRNA Anatgomir 以促进血管自身
  • 批准号:
    8138278
  • 财政年份:
    2011
  • 资助金额:
    $ 48.94万
  • 项目类别:
SCID Mouse: Human Xenograft Core
SCID 小鼠:人类异种移植核心
  • 批准号:
    7608570
  • 财政年份:
    2008
  • 资助金额:
    $ 48.94万
  • 项目类别:

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