INHIBITION OF C-MYC TO TREAT POLYCYSTIC KIDNEY DISEASE

抑制 C-MYC 治疗多囊肾病

• 批准号: 6143960
• 负责人: PATRICK L IVERSEN
• 金额: $ 9.84万
• 依托单位: AVI BIOPHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6143960
• 关键词: amidation /deamidation; antisense nucleic acid; drug design /synthesis /production; drug screening /evaluation; gene induction /repression; histopathology; kidney disorder chemotherapy; laboratory mouse; laboratory rat; oligonucleotides; phosphorus; polycystic kidney; protooncogene; western blottings

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.

建议开发一种治疗多囊肾病（PKD）的药物疗法。多囊肾 (PKD) 是最常见的人类遗传病，影响美国约 50 万人。 在模拟人类疾病的啮齿动物 PKD 模型中，原癌基因 c-myc 的过度表达已被证明是囊肿发育不可或缺的一部分。 我们提出这样的假设：使用与 c-myc mRNA AUG 翻译起始位点 (AVI-4126) 互补的磷酸二酰胺吗啉代寡核苷酸 (PMO) 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再狭窄。使用 AVI-4126 治疗 PKD 是一种治疗多囊肾疾病的新方法，目前尚无有效药物可治疗该疾病。 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。我们提出的研究概述了以下四个目标：l) 评估 PMO 接触肾囊肿上皮适当细胞的能力，2.) 评估 C57BL/6J-cpk 小鼠中反义 PMO 对 c-myc 的抑制作用，以及 3.) 评估 Balb-c-cpk 小鼠中反义 PMO 对 c-myc 的抑制作用4.) 评估 Han:SPRD 大鼠中的反义 PMO。 拟议的研究如果成功，将导致提出第二阶段资助提案，以将 AVI-4126 的使用带入药品市场。拟议的商业应用：本提案中概述的研究旨在测试目前正在 PKD 模型中评估再狭窄和成骨肉瘤的化合物。 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 治疗的侵入性姑息治疗提供一种廉价的替代方案。第一阶段的疗效证据将导致第二阶段临床前开发的提议。