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 β 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 β 1似乎是治疗慢性肾脏疾病的一个有前途的靶点。然而，TGF？具有深刻的抗炎特性，并且TGF β基因缺陷的动物在出生后不久死于压倒性的炎症，提出了全身性TGF β阻断可能具有严重炎症副作用的可能性。不幸的是，TGF β阻断的所有人类临床试验都受到其潜在的全身副作用的阻碍。TGF的靶向递送对纤维化肾小球的阻断提供了新的治疗方法，而没有显著的全身性副作用。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siRNA-纳米载体系统。该纳米载体在靶向递送针对肾素受体基因的siRNA至大鼠肾炎肾小球中显示出有希望的效率和特异性，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用于靶向系膜细胞的基于纳米颗粒的SiRNA治疗肾小球纤维化的可行性。我们建议使用TGF？1-Steath siRNA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地沉默靶TGF β 1;（2）肾小球系膜细胞中TGF β 1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靶向肾小球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治疗。为了验证我们的假设，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减TGF ² 1基因表达;目标2：研究纳米载体递送的体内治疗潜力在实验性肾小球肾炎中，肾小球局部存在高水平的TGF ² 1。成功地进行，我们的研究将提供概念验证，siRNA可以选择性地通过自组装纳米载体传递到系膜细胞。这一新的策略将是关键的肾小球纤维化的发展和进展的研究。它还将对肾小球靶向抗TGF β 1 siRNA分子的开发产生重大影响，作为一种新的辅助疗法，以克服肾小球纤维化的全身性不良反应，但克服全身性不良反应，可能有助于对抗目前慢性肾脏疾病的流行。公共卫生关系：转化生长因子1作为治疗慢性肾脏疾病的有希望的靶点，具有深刻的抗炎特性，这可能会阻碍所有全身性TGF β 1阻断的临床试验。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递送的系膜细胞特异性、配体靶向、自组装siRNA-纳米载体系统。该纳米载体在靶向递送针对肾素受体基因的siRNA至大鼠肾炎肾小球中显示出有希望的效率和特异性，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用于肾小球纤维化的系膜细胞靶向的基于纳米颗粒的抗TGF <$1 siRNA疗法的可行性。我们建议（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;（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，其中肾小球中局部存在高水平的TGF <$1。成功地进行，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治疗，但克服了全身性不良反应，可能有助于对抗目前慢性肾脏疾病的流行。