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Targeted delivery of TGFbeta blockade to diseased glomeruli

将 TGFbeta 阻断剂靶向递送至患病肾小球

基本信息

批准号：
7914416
负责人：
yufeng huang
金额：
$ 22.58万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-13 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7914416
关键词：
Adjuvant Therapy Adverse effects Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antibodies Birth Cells Chronic Kidney Failure Clinical Trials Cytolysis Development End stage renal failure Epidemic Fibrosis Gene Delivery Gene Expression Gene Silencing Glomerular Mesangial Cell Glomerulonephritis Goals Healthcare Human In Vitro Incidence Inflammation Inflammatory Innovative Therapy Kidney Kidney Diseases Kidney Failure Ligands Measures Mediator of activation protein Molecular Molecular Target Organ Prevalence Property RNA Interference Rattus Receptor Gene Renal glomerular disease Renin Research Role Site Small Interfering RNA Specificity System Technology Testing Therapeutic Thy-1 Antigens Tissues Transfection Transforming Growth Factor beta anti-Thy-1 base combat decorin gene delivery system human TGFB1 protein human disease in vivo knock-down mesangial cell nanobiotechnology nanoparticle nanovector neutralizing antibody novel novel strategies novel therapeutic intervention overexpression public health relevance receptor success targeted delivery tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The incidence and prevalence of end-stage renal disease is increasing at an alarming rate, new innovative therapies for halting the progress of chronic renal failure are urgently demanded. Overexpression of transforming growth factor-beta 1 (TGF¿1) is the most common molecular feature of progressive renal disease. It has been identified as a primary key mediator and quantifiable measure of fibrotic renal disease. TGF¿1 appears to be a promising target for treatment of chronic renal disease. However, that TGF¿ has profound anti-inflammatory properties and that animals genetically deficient in TGF¿ die of overwhelming inflammation shortly after birth, raises the possibility that systemic TGF¿ blockade may have serious inflammatory side effects. All human clinical trials of TGF¿ blockade are unfortunately hampered by its potential systemic side effects. Targeted delivery of TGF¿ blockade to fibrotic glomeruli offers novel therapeutic approaches for treatment without noteworthy systemic adverse effects. By combining small interfering RNA (siRNA) with nanoparticle technology, we have recently developed a mesangial cell-specific, ligand-targeting, self- assembled siRNA-nanovector system for gene delivery. The nanovectors show promising efficiency and specificity in targeted delivery of siRNA against the renin receptor gene to nephritic glomeruli in rat, with limited effect on other tissues. The objective of this R21 exploratory project proposal is to explore the feasibility of using our novel nanovector system for mesangial cell targeted nanoparticle-based siRNA therapeutics for glomerular fibrosis. We propose to use TGF¿1-Steath siRNA to test two inter-related hypotheses: (1) the self- assembled nanovectors can selectively deliver siRNA to glomerular mesangial cells and efficiently silence the target TGF¿1; (2) Specifically silencing of TGF¿1 in glomerular mesangial cells will ameliorate the progression of matrix expansion in experimental glomerulonephritis. Our long-term goal is to develop the mesangial cell- targeting nanoparticle-based siRNA as novel molecular therapy for glomerular disease. To test our hypothesis, we propose to carry out two Specific Aims: Aim 1: To prepare and optimize nanovectors for efficient knock- down of TGF¿1 gene expression by RNA interference both in vitro and in vivo; Aim 2: To investigate the in vivo therapeutic potential of nanovector-delivered RNAi in experimental glomerulonephritis where high levels of TGF¿1 occur locally in glomeruli. Successfully carried out, our study will provide proof-of-concept that siRNA can be selectively delivered to mesangial cells by the self-assembled nanovectors. This novel strategy will be critical for the studies in glomerular fibrosis development and progression. It also will have a significant impact on the development of a glomerulus-targeted anti-TGF¿1 siRNA molecule as a novel adjuvant therapy to overcome systemic adverse effects for glomerular fibrosis but overcomes systemic adverse effects that may help combat the current epidemic in chronic kidney disease. PUBLIC HEALTH RELEVANCE: TGF¿1, as a promising target for treatment of chronic renal disease, has profound anti-inflammatory properties, which may hamper all clinical trials of systemic TGF¿1 blockade. By combining small interfering RNA (siRNA) with nanoparticle technology, we have recently developed a mesangial cell-specific, ligand- targeting, self-assembled siRNA-nanovector system for gene delivery. The nanovectors show promising efficiency and specificity in targeted delivery of siRNA against the renin receptor gene to nephritic glomeruli in rat, with limited effect on other tissues. The objective of this R21 exploratory project proposal is to explore the feasibility of using our novel nanovector system for mesangial cell targeted nanoparticle-based anti-TGF¿1 siRNA therapeutics for glomerular fibrosis. We propose to (1) prepare and optimize nanovectors for efficient knockdown of TGF¿1 gene expression by RNA interference in vitro and in vivo; (2) investigate the in vivo therapeutic potential of nanovector-delivered RNAi in experimental glomerulonephritis where high levels of TGF¿1 occur locally in glomeruli. Successfully carried out, our studies will have a significant impact on the development of an organ-targeted anti-TGF¿1 siRNA molecule as a novel adjuvant therapy for glomerular fibrosis but overcomes systemic adverse effects that may help combat the current epidemic in chronic kidney disease.

描述（申请人提供）：终末期肾病的发病率和患病率正在以惊人的速度增加，迫切需要新的创新疗法来阻止慢性肾衰竭的进展。转化生长因子-β 1 (TGF¿1) 的过度表达是进行性肾病最常见的分子特征。它已被确定为纤维化肾病的主要关键介质和可量化指标。 TGF¿1 似乎是治疗慢性肾病的有希望的靶标。然而，TGF 具有深远的抗炎特性，并且遗传性缺乏 TGF 的动物在出生后不久就会死于严重的炎症，这增加了全身性 TGF 阻断可能产生严重炎症副作用的可能性。不幸的是，所有 TGF 阻断剂的人体临床试验都因其潜在的全身副作用而受到阻碍。对纤维化肾小球进行 TGF 阻断的靶向递送提供了新的治疗方法，且没有显着的全身不良反应。通过将小干扰RNA（siRNA）与纳米颗粒技术相结合，我们最近开发了一种用于基因递送的系膜细胞特异性、配体靶向、自组装的siRNA纳米载体系统。纳米载体在将针对肾素受体基因的 siRNA 靶向递送至大鼠肾小球方面表现出良好的效率和特异性，而对其他组织的影响有限。该 R21 探索性项目提案的目的是探索使用我们的新型纳米载体系统进行基于肾小球纤维化的肾小球细胞靶向纳米颗粒 siRNA 治疗的可行性。我们建议使用TGF¿1-Steath siRNA来测试两个相互关联的假设：（1）自组装纳米载体可以选择性地将siRNA递送至肾小球系膜细胞并有效沉默靶标TGF¿ (2) 肾小球系膜细胞中 TGFβ1 的特异性沉默将改善实验性肾小球肾炎中基质扩张的进展。我们的长期目标是开发基于纳米粒子的肾小球系膜细胞靶向 siRNA，作为肾小球疾病的新型分子疗法。为了检验我们的假设，我们建议实现两个具体目标：目标 1：制备和优化纳米载体，通过 RNA 干扰在体外和体内有效敲低 TGF¿1 基因表达；目标 2：研究纳米载体递送的 RNAi 在实验性肾小球肾炎中的体内治疗潜力，其中肾小球局部存在高水平的 TGF-1。如果成功进行，我们的研究将提供概念证明，即 siRNA 可以通过自组装纳米载体选择性地递送至系膜细胞。这种新策略对于肾小球纤维化发生和进展的研究至关重要。它还将对肾小球靶向抗 TGF-β1 siRNA 分子的开发产生重大影响，作为一种新型辅助疗法，以克服肾小球纤维化的全身不良反应，但克服可能有助于对抗当前慢性肾病流行的全身不良反应。公共健康相关性：TGF¿1 作为治疗慢性肾病的一个有前景的靶标，具有深远的抗炎特性，这可能会阻碍全身性 TGF¿1 阻断的所有临床试验。通过将小干扰RNA（siRNA）与纳米颗粒技术相结合，我们最近开发了一种用于基因递送的系膜细胞特异性、配体靶向、自组装的siRNA纳米载体系统。纳米载体在将针对肾素受体基因的 siRNA 靶向递送至大鼠肾小球方面表现出良好的效率和特异性，而对其他组织的影响有限。该 R21 探索性项目提案的目的是探索使用我们的新型纳米载体系统进行基于系膜细胞靶向纳米颗粒的抗 TGF-1 siRNA 治疗肾小球纤维化的可行性。我们建议 (1) 制备和优化纳米载体，通过体内外 RNA 干扰有效敲低 TGF¿1 基因表达； (2) 研究纳米载体递送的 RNAi 在实验性肾小球肾炎中的体内治疗潜力，其中肾小球局部出现高水平的 TGF-1。如果成功进行，我们的研究将对器官靶向抗 TGF¿1 siRNA 分子的开发产生重大影响，作为肾小球纤维化的新型辅助疗法，但克服全身性副作用，可能有助于对抗当前慢性肾病的流行。