INHIBITION OF C-MYC TO TREAT POLYCYSTIC KIDNEY DISEASE

提出了一种治疗多囊肾病（PKD）的药物疗法。PKD是最常见的人类遗传疾病，在美国大约有50万人受到影响。原癌基因c-myc的过度表达已被证明是模拟人类疾病的啮齿动物PKD模型中囊肿发展的组成部分。我们提出假设，使用与c-myc mRNA AUG翻译起始位点（AVI-4126）互补的磷酸二酯morpholino寡核苷酸（PMOs）抑制c-myc表达将阻止或减缓PKD的进展。该化合物目前正处于临床前开发阶段，用于治疗成骨肉瘤和血管狭窄症。使用AVI-4126治疗PKD是目前没有有效药物治疗基础疾病的一种新方法。AVI-4126在人类疾病小鼠模型中的初步结果表明安全性和有效性。我们建议进行以下四个目标的研究：1)评估PMOs进入肾囊肿上皮适当细胞的能力；2)2 .反义PMOs对C57BL/6J-cpk小鼠c-myc抑制作用的评价；反义PMOs对Balb-c-cpk小鼠c-myc抑制作用的评价反义PMOs对汉族SPRD大鼠c-myc抑制作用的评价。这项研究如果成功，将会申请二期资金，将AVI-4126推向药物市场。拟议的商业应用：本提案中概述的研究旨在测试一种化合物，目前正在评估PKD模型中血管狭窄和成骨性肉瘤的疗效。该提案的目的是测试将AVI-4126或其他反义化合物引入药物市场的可行性，并为PKD治疗提供一种廉价的替代侵入性姑息治疗方法。I期疗效的证据将导致I期临床前开发的建议。

Development of a drug therapy to treat polycystic kidney disease (PKD) is proposed. PKD is the most common human genetic disease affecting approximately one half million people in the USA. The over-expression of the proto-oncogene c-myc has been shown to be integral to cyst development in rodent PKD models which mimic the human disease. We propose the hypothesis that inhibition of c-myc expression using phosphorodiamidate morpholino oligonucleotides (PMOs) complementary to c-myc mRNA AUG translation start site (AVI-4126) will stop or slow progression of PKD. This compound is currently in preclinical development for use in the treatment of osteogenic sarcoma and restinosis. The use of AVI-4126 in the treatment of PKD is a novel approach to a disease for which there are currently no effective drugs for treatment of the underlying disease. Preliminary results with AVI-4126 in a mouse model of human disease suggests both safety and efficacy. We propose studies outlined by the following four aims: l) Evaluate the ability of PMOs to gain access to the appropriate cells of the renal cyst epithelium, 2.) Evaluation of inhibition of c-myc by antisense PMOs in C57BL/6J-cpk mice, and 3.) Evaluation of inhibition of c-myc by antisense PMOs in Balb-c-cpk mice 4.) Evaluation of inhibition of c-myc by antisense PMOs in Han:SPRD rats. The proposed research, if successful, would lead to a proposal for Phase II funding to bring the use of AVI-4126 into the drug market. PROPOSED COMMERCIAL APPLICATIONS: The studies outlined in this proposal are designed to test a compound currently being evaluated for restinosis and osteogenic sarcoma in a model of PKD. The intent of this proposal is to test the feasibility of bringing AVI-4126 or other antisense compounds into the drug market and provide an inexpensive alternative to invasive palliative procedures for PKD treatment. Evidence of efficacy in Phase I will lead to a proposal for preclinical development in Phase Il.