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: 10197784
• 负责人: JORDAN S POBER
• 金额: $ 48.94万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10197784
• 关键词: Acute; Address; Alleles; Allografting; Antibodies; Antibody titer measurement; Antibody-Producing Cells; Antigen Targeting; Antigens; Arteries; Binding; Biochemical; Blood; Blood Vessels; Blood capillaries; Body Temperature; Caliber; Cell Culture Techniques; Cells; Chronic; Clinical; Clinical Trials; Collaborations; Complement; Complement Activation; Complement Membrane Attack Complex; Data; Deposition; Development; Dose; Drug Delivery Systems; Early Endosome; Endothelial Cells; Endothelium; Erythrocytes; Ethics; Excision; Funding; Gamma globulin; Genes; Goals; Graft Survival; Grant; HLA Antigens; Harvest; Histocompatibility; Hour; Human; Immune; Immunodeficient Mouse; In Situ; In Vitro; Individual; Inflammation; Infusion procedures; Injury; Intervention; Intravenous; Intravenous Immunoglobulins; Ischemia; Kidney; Kidney Failure; Kidney Transplantation; Leukocytes; Mediating; Membrane Proteins; Methods; Microfluidics; Mus; Organ; Organ Harvestings; Outcome; PECAM1 gene; Patients; Perfusion; Perioperative; Pharmaceutical Preparations; Plasmapheresis; Polymers; Population; Postoperative Period; Prevention; Process; Protective Agents; Protein-Serine-Threonine Kinases; Proteins; Pump; Reagent; Recovery; Research; Resistance; Risk Factors; Signal Pathway; Signal Transduction; Small Interfering RNA; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Time; Transplant Recipients; Transplantation; Transplantation Surgery; United States National Institutes of Health; Universities; Validation; Vascular Endothelial Cell; anti-endothelial cell antibody; antibody conjugate; base; cell injury; cell type; cost; drug candidate; experimental study; fluorophore; gene product; graft failure; humanized mouse; immunoregulation; improved; improved outcome; in vivo; inflammatory milieu; inhibitor/antagonist; kidney allograft; kidney vascular structure; mouse model; nanomedicine; nanoparticle; nanoparticle delivery; nanoparticle drug; neutrophil; novel strategies; pre-clinical; prevent; recruit; response; small molecule; small molecule therapeutics; success; targeted delivery; targeted treatment

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

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: The American journal of pathology
• 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: MOLECULAR PHARMACEUTICS
• 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: SCIENCE TRANSLATIONAL MEDICINE
• 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: Nature communications
• 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: Science translational medicine
• 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