权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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(申请人提供)：膀胱内注入小干扰RNA(SiRNAs)是一种令人兴奋的泌尿系统疾病的新治疗选择。由于基因选择性沉默靶蛋白的表达，siRNA寡核苷酸因其高度的选择性和特异性而成为一种有吸引力的治疗选择。然而，siRNAs的半衰期相对较短，因此我们将解决siRNAs的稳定和膀胱内递送的技术挑战。为了实现这一目标，我们计划创造并测试临床上可行的、非病毒的纳米球-siRNA复合体，这些复合体被膀胱内灌输，用于治疗膀胱癌和其他尿路疾病。我们已经：1)开发了过表达膀胱特异的人Survivin并且与特定基因签名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都上调了；3)与Mark Saltzman博士合作开发了用于药物输送的聚丙交酯-乙交酯(PLGA)纳米微球，我们处于独特的地位来确定siRNA-PLGA在小鼠疾病模型中的作用，该模型将在我们的转基因和膀胱癌模型中进行初步测试。具体地说，我们计划：1)开发和测试siRNA控制释放系统，以稳定和传递siRNA；2)在整个动物系统中测试微囊化人Survivin siRNA选择性逆转转基因诱导的膀胱特异性Survivin及其相关基质和炎症变化的能力；3)在亚硝胺诱导的膀胱癌模型中，测试微囊化Survivin siRNA和VEGFsiRNA联合使用是否比单独使用微囊化siRNAs更有效地降低肿瘤负担、缩短发病时间、降低发病率和死亡率。因此，使用包裹在微球中的siRNA可以解决更有效的膀胱内灌注方案治疗包括膀胱癌、膀胱过度活动症和IC在内的常见泌尿系统疾病的挑战，以增加其稳定性和延长其疗效。对于包括膀胱癌、膀胱过度活跃和间质性膀胱炎在内的泌尿系统疾病，标准的药物和化疗方案可能会导致不良副作用或无效。小干扰RNA(SiRNA)可以特异性和灵敏地降解RNA信息，从而降低其靶蛋白水平。为了挖掘这些短命且容易降解的siRNAs的治疗潜力，我们设计了稳定和测试这些siRNAs的策略。然后，这些siRNA聚合物将被注入到膀胱癌的小鼠模型中，作为膀胱癌的治疗方法。此外，为了针对不同的癌症途径，可以在膀胱内注入不止一种siRNA。因此，我们可以确定siRNA在治疗泌尿系统疾病方面的治疗潜力。