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
- 来源:
- 关键词:AcuteAddressAllelesAllograftingAntibodiesAntibody titer measurementAntibody-Producing CellsAntigen TargetingAntigensArteriesBindingBiochemicalBloodBlood VesselsBlood capillariesBody TemperatureCaliberCell Culture TechniquesCellsChronicClinicalClinical TrialsCollaborationsComplementComplement ActivationComplement Membrane Attack ComplexDataDepositionDevelopmentDoseDrug Delivery SystemsEarly EndosomeEndothelial CellsEndotheliumErythrocytesEthicsExcisionFundingGamma globulinGenesGoalsGraft SurvivalGrantHLA AntigensHarvestHistocompatibilityHourHumanImmuneImmunodeficient MouseIn SituIn VitroIndividualInflammationInfusion proceduresInjuryInterventionIntravenousIntravenous ImmunoglobulinsIschemiaKidneyKidney FailureKidney TransplantationLeukocytesMediatingMembrane ProteinsMethodsMicrofluidicsMusOrganOrgan HarvestingsOutcomePECAM1 genePatientsPerfusionPerioperativePharmaceutical PreparationsPlasmapheresisPolymersPopulationPostoperative PeriodPreventionProcessProtective AgentsProtein-Serine-Threonine KinasesProteinsPumpReagentRecoveryResearchResistanceRisk FactorsSignal PathwaySignal TransductionSmall Interfering RNAT-LymphocyteTestingTherapeuticTherapeutic AgentsTimeTransplant RecipientsTransplantationTransplantation SurgeryUnited States National Institutes of HealthUniversitiesValidationVascular Endothelial Cellanti-endothelial cell antibodyantibody conjugatebasecell injurycell typecostdrug candidateexperimental studyfluorophoregene productgraft failurehumanized mouseimmunoregulationimprovedimproved outcomein vivoinflammatory milieuinhibitor/antagonistkidney allograftkidney vascular structuremouse modelnanomedicinenanoparticlenanoparticle deliverynanoparticle drugneutrophilnovel strategiespre-clinicalpreventrecruitresponsesmall moleculesmall molecule therapeuticssuccesstargeted deliverytargeted treatment
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.
肾衰竭患者中有很大一部分是肾移植的受益者,
预致敏的,即它们具有高滴度的预形成的循环抗体(Ab),其与80%或更多的
I类和/或II类HLA抗原的非自身等位基因形式,称为群体反应性Ab(PRA)。后
移植后,宿主PRA将结合移植物内皮细胞上高度表达的移植物HLA抗原
(ECs)在那里它们激活宿主人补体,导致膜攻击复合物(MAC)的沉积,
在EC上。人MAC不裂解人EC,而是改变它们以表达基因产物,
促进炎症。炎症环境有利于适应性免疫效应子的激活,
保护性免疫调节。因此,如果移植,高滴度PRA的患者增加了
急性和慢性排斥反应的发作导致更多的移植物衰竭和移植物损失。当前治疗
方法包括血浆置换以降低循环PRA的滴度,靶向消除产生Ab的抗体,
细胞和/或给予高剂量静脉注射丙种球蛋白以减少炎症,但PRA滴度
这些干预措施对结果的影响有限。我们提出了一种新的策略,
补充这些方法,即通过减少移植物EC对PRA/MAC的反应来减少移植物EC对PRA/MAC的反应。
HLA抗原靶向表达和/或通过抑制EC中的PRA/MAC信号传导。后一种方法
基于我们对相关信号通路的阐明。为了实现这一目标,我们将发展安全、
- 聚合物纳米颗粒(NP),其通过缀合的抗EC Ab靶向移植物EC,
使用这些NP在离体期间递送siRNA或小分子治疗剂(“药物”),
常温灌注(EVNP),一种用于改善肾脏能量储存的方法,
在移植前从死亡的捐赠者身上提取器官。这些NP将被绑定并内化
通过移植物EC,然后将作为治疗剂持续释放足够长时间的贮库
以允许移植物调节和/或宿主免疫调节发展。在特定目标1中,我们将使用人类
将EC培养物和人动脉段插入免疫缺陷小鼠的动脉中,以鉴定
最佳的siRNA或药物可以保护EC免受PRA的影响。我们最初的目标将是防止Akt激活,
PRA/MAC信令中的关键步骤。在特定目标2中,我们将确定靶向肾脏人EC的最佳Ab
并使用这些来确定在不适合临床应用的人肾脏中有效的泛EC递送的条件,
由我们的合作者在剑桥大学进行EVNP。(U01支持
将仅用于在耶鲁大学进行的实验和分析;实验EVNP的成本将是
由我们的剑桥同事提供,他们得到了英国国家卫生研究所的资助。
EVNP的研究和实验将在剑桥大学进行,
核准。如果成功,这种方法可以扩展到其他用途,并可以证明人体临床试验的合理性。
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.
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
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
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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:
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