Encapsulated siRNAs for treatment of urological disease

用于治疗泌尿系统疾病的封装 siRNA

基本信息

批准号：
7481032
负责人：
ROBERT M WEISS
金额：
$ 24.33万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-07 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7481032
关键词：
Address Adverse effects Animal Disease Models Animal Model Animals Base Pairing Bladder Cancer Model Cancer cell line Cells Collaborations Communicable Diseases Complex Disease model Down-Regulation Drug Delivery Systems Encapsulated Engineering Extracellular Matrix Fluorescein Fluoresceins Genes Glycolic-Lactic Acid Polyester Goals Half-Life Human Hyperreflexia Immune Immunotherapy In Vitro Individual Inflammatory Inflammatory Response Interstitial Cystitis Intravesical Instillation Label Life Malignant Neoplasms Malignant neoplasm of urinary bladder Measures Messenger RNA Microspheres Modeling Mus Nanosphere Nitrosamines Oligonucleotides Overactive Bladder Parathyroid Hormones Pathway interactions Penetration Polymers Positioning Attribute Protein Overexpression Proteins Protocols documentation RNA RNA Interference RNA Stability Rate Scanning Electron Microscopy Site Small RNA Specificity Standards of Weights and Measures System Techniques Testing Therapeutic Time Toxic effect Transcriptional Activation Transgenic Mice Transgenic Organisms Treatment Protocols Tumor Burden Up-Regulation Urologic Diseases Urothelium Vascular Endothelial Growth Factors Viral bladder transitional cell carcinoma cancer cell chemotherapy controlled release day design drug efficacy gene therapy human PTH protein in vivo intravesical mortality mouse model polylactic acid-polyglycolic acid copolymer professor protein expression survivin tool tumor uptake

项目摘要

DESCRIPTION (provided by applicant): Intravesical instillation of small interference RNAs (siRNAs) is an exciting new treatment option for urological diseases. siRNA oligonucleotides are an attractive therapeutic option because of their high selectivity and specificity, due to gene selective silencing of target protein expression. siRNAs, however, have a relatively short half-life and thus we will address the technical challenges of stabilization and intravesical delivery of siRNAs. To achieve this goal, we plan to create and test clinically viable, non-viral nanosphere- siRNA complexes that are intravesically instilled for treatment of bladder cancer and other diseases of the urinary tract. As we have: 1) developed transgenic mice that over- express bladder specific human survivin and that is associated with transcriptional activation of a specific gene signature; 2) established a nitrosamine induced murine bladder cancer model in which both survivin and VEGF are upregulated; and 3) developed, in collaboration with Dr.W. Mark Saltzman Professor and Chair, Department of Bio-engineering, poly (lactide-co-glycolide (PLGA) nanospheres for drug delivery, we are in an unique position to determine the effect of intravesical instillation of siRNA- PLGA in mouse disease models which will initially be tested in our transgenic and bladder cancer models. Specifically we plan to: 1) develop and test a siRNA controlled release system to stabilize and deliver siRNA; 2) test in a whole animal system, the ability of intravesically instilled microencapsulated human survivin siRNA to selectively reverse upregulation of transgenically induced bladder specific survivin and the matrix and inflammatory changes associated with survivin upregulation; and 3) test whether the combination of encapsulated survivin siRNA and VEGF siRNA more effectively reduces tumor burden, the time to onset, rate of occurrence and mortality than individual encapsulated siRNAs in a nitrosamine induced bladder cancer model. Thus, the challenges of more effective intravesical instillation protocols for treatment of common urological diseases including bladder cancer, overactive bladder and IC can be addressed using siRNAs encapsulated in microspheres to increase their stability and prolong their efficacy. Standard pharmacologic and chemotherapeutic treatment options for urological diseases including bladder cancer, overactive bladder and interstitial cystitis may cause undesirable side effects or may be ineffective. Small interference RNA (siRNA) can specifically and sensitively degrade RNA messages and thus reduce their target protein levels. In order to exploit the therapeutic potential of these siRNAs, which are short lived and easily degraded, we have designed strategies for stabilization and testing of these siRNAs. Then, these siRNA polymers will be intravesically instilled as a treatment for bladder cancer, using mouse models of bladder cancer. Furthermore, more than one siRNA can be intravesically instilled in order to target different cancer pathways. Thus, we can determine the therapeutic potential of siRNA for treatment of urologic diseases.

描述（由申请人提供）：小型干扰RNA（SIRNA）的静脉注入是泌尿外科疾病的令人兴奋的新治疗方法。 siRNA寡核苷酸是一种有吸引力的治疗选择，因为它们的选择性高和特异性，由于基因选择性沉默靶蛋白表达。但是，siRNA的半衰期相对较短，因此我们将解决siRNAS稳定和静脉内输送的技术挑战。为了实现这一目标，我们计划创建和测试临床上可行的非病毒纳米siRNA复合物，这些复合物是插入的，用于治疗膀胱癌和尿路的其他疾病。正如我们所拥有的：1）开发了过度表达膀胱特异性人类生存的转基因小鼠，并且与特定基因特征的转录激活有关； 2）建立了硝基胺诱导的鼠膀胱癌模型，其中survivin和vegf均被上调；和3）与W. Dr.W.合作开发马克·萨尔茨曼（Mark Saltzman）教授兼生物工程系，聚（乳酸 - 糖糖苷（PLGA）纳米球进行药物输送，我们处于一个独特的位置，可以确定在小鼠疾病模型中对小鼠疾病中的sirna-plga插入sirna-plga的效果2）在整个动物系统中测试，插入式灌输的微封装的人类Survivin siRNA有选择地逆转转基因诱导的膀胱特异性生存的能力以及与Survivin上调相关的基质和炎症变化的能力； 3）测试封装的Survivin siRNA和VEGF siRNA的组合是否比硝基胺诱导的膀胱癌模型中的单个封装的siRNA相比，更有效地减少了肿瘤负担，发作的时间，发生率和死亡率。因此，可以使用封装在微球中提高其稳定性并延长其功效的siRNA来解决更有效的经扰性灌注方案的挑战，包括膀胱癌，过度活跃的膀胱和IC在内的常见泌尿外科疾病的挑战。泌尿科疾病，包括膀胱癌，过度活跃和间质膀胱炎在内的标准药理学和化学治疗方案可能会导致不良的副作用或可能无效。小干扰RNA（siRNA）可以特异性和灵敏地降解RNA消息，从而降低其靶蛋白水平。为了利用这些siRNA的治疗潜力，这些siRNA是短暂的且容易降解的，我们设计了这些siRNA的稳定和测试的策略。然后，使用膀胱癌的小鼠模型，将这些siRNA聚合物在插入术中被灌输为膀胱癌的治疗方法。此外，为了靶向不同的癌症途径，可以插入室内灌输多个siRNA。因此，我们可以确定siRNA治疗泌尿科疾病的治疗潜力。