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：
7238990
负责人：
ROBERT M WEISS
金额：
$ 20.63万
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 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7238990
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）：小干扰 RNA (siRNA) 的膀胱内滴注是泌尿系统疾病的一种令人兴奋的新治疗选择。 siRNA 寡核苷酸是一种有吸引力的治疗选择，因为它们通过基因选择性沉默靶蛋白表达而具有高选择性和特异性。然而，siRNA 的半衰期相对较短，因此我们将解决 siRNA 的稳定性和膀胱内递送的技术挑战。为了实现这一目标，我们计划创建并测试临床上可行的非病毒纳米球-siRNA复合物，将其膀胱内滴注用于治疗膀胱癌和其他泌尿道疾病。正如我们所拥有的：1）开发出过度表达膀胱特异性人类生存素并且与特定基因特征的转录激活相关的转基因小鼠； 2)建立了亚硝胺诱导的小鼠膀胱癌模型，其中survivin和VEGF均上调； 3) 与 Dr.W. 合作开发。 Mark Saltzman 教授兼生物工程系系主任，用于药物输送的聚丙交酯-乙交酯 (PLGA) 纳米球，我们处于独特的地位，可以确定 siRNA-PLGA 膀胱内滴注在小鼠疾病模型中的效果，这将最初在我们的转基因和膀胱癌模型中进行测试，具体来说，我们计划：1）开发和测试 siRNA 控释系统以稳定和递送 siRNA； 2)在整个动物系统中测试膀胱内滴注微囊化人生存素siRNA选择性逆转转基因诱导的膀胱特异性生存素上调以及与生存素上调相关的基质和炎症变化的能力； 3)测试在亚硝胺诱导的膀胱癌模型中，封装的生存素siRNA和VEGF siRNA的组合是否比单独封装的siRNA更有效地降低肿瘤负荷、发病时间、发生率和死亡率。因此，使用封装在微球中的 siRNA 来提高其稳定性并延长其疗效，可以解决更有效的膀胱内灌注方案用于治疗膀胱癌、膀胱过度活动症和 IC 等常见泌尿系统疾病的挑战。泌尿系统疾病（包括膀胱癌、膀胱过度活动症和间质性膀胱炎）的标准药物和化疗治疗方案可能会导致不良副作用或可能无效。小干扰RNA (siRNA) 可以特异性、灵敏地降解RNA 信息，从而降低其目标蛋白水平。为了开发这些寿命短且容易降解的 siRNA 的治疗潜力，我们设计了稳定和测试这些 siRNA 的策略。然后，使用膀胱癌小鼠模型将这些 siRNA 聚合物注入膀胱内以治疗膀胱癌。此外，可以将不止一种 siRNA 注入膀胱内，以针对不同的癌症途径。因此，我们可以确定 siRNA 治疗泌尿系统疾病的潜力。