Targeted delivery of TGFbeta blockade to diseased glomeruli

将 TGFbeta 阻断剂靶向递送至患病肾小球

• 批准号: 7659933
• 负责人: yufeng huang
• 金额: $ 18.81万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-13 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7659933
• 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

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（由申请人提供）：终末期肾脏疾病的发病率和患病率正以惊人的速度增加，迫切需要新的创新疗法来阻止慢性肾功能衰竭的进展。转化生长因子- β 1 （TGF¿1）的过度表达是进展性肾脏疾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的措施。TGF¿1似乎是治疗慢性肾脏疾病的一个有希望的靶点。然而，TGF¿具有深刻的抗炎特性，TGF¿基因缺乏的动物在出生后不久就死于严重的炎症，这提高了系统性TGF¿阻断可能具有严重炎症副作用的可能性。不幸的是，TGF -阻滞剂的所有人体临床试验都因其潜在的全身副作用而受阻。靶向递送TGF -阻滞剂到纤维化肾小球提供了新的治疗方法，没有明显的全身不良反应。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传递的系膜细胞特异性、配体靶向、自组装的siRNA纳米载体系统。纳米载体在将siRNA靶向肾素受体基因递送至大鼠肾小球方面显示出良好的效率和特异性，但对其他组织的影响有限。这个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用于肾小球纤维化的系膜细胞靶向纳米颗粒siRNA治疗的可行性。我们提出利用TGF - 1- steath siRNA来验证两个相互关联的假设：(1)自组装的纳米载体可以选择性地将siRNA传递到肾小球系膜细胞，并有效地沉默靶TGF - 1；(2)特异性沉默肾小球系膜细胞TGF¿1可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靶向系膜细胞的基于纳米颗粒的siRNA作为肾小球疾病的新型分子疗法。为了验证我们的假设，我们提出了两个具体的目标：目标1：制备和优化纳米载体，在体外和体内通过RNA干扰有效地敲低TGF - 1基因的表达；目的2：探讨纳米载体递送的RNAi在实验性肾小球肾炎（肾小球局部高水平TGF¿1）中的体内治疗潜力。如果成功进行，我们的研究将提供概念证明，siRNA可以通过自组装的纳米载体选择性地传递到系膜细胞。这一新策略将对肾小球纤维化的发展和进展的研究至关重要。它还将对肾小球靶向抗tgf¿1 siRNA分子的发展产生重大影响，作为一种新的辅助治疗方法，克服肾小球纤维化的全身不良反应，但克服全身不良反应可能有助于对抗当前流行的慢性肾脏疾病。公共卫生相关性：TGF¿1作为治疗慢性肾脏疾病的一个有前景的靶点，具有深刻的抗炎特性，这可能会阻碍所有系统性阻断TGF¿1的临床试验。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传递的系膜细胞特异性、配体靶向、自组装的siRNA纳米载体系统。纳米载体在将siRNA靶向肾素受体基因递送至大鼠肾小球方面显示出良好的效率和特异性，但对其他组织的影响有限。这项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用于肾小球纤维化的系膜细胞靶向纳米颗粒抗tgf¿1 siRNA治疗的可行性。我们提出(1)制备并优化纳米载体，在体外和体内通过RNA干扰有效下调TGF - 1基因的表达；(2)研究纳米载体递送RNAi在实验性肾小球肾炎（肾小球局部高水平TGF¿1）中的体内治疗潜力。如果成功开展，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一种新型辅助治疗方法，同时克服全身不良反应，可能有助于对抗当前慢性肾脏疾病的流行。