Development of modified microRNA therapeutics

改良 microRNA 疗法的开发

基本信息

批准号：
8001492
负责人：
DAVID M BROWN
金额：
$ 28.73万
依托单位：
MIRNA THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8001492
关键词：
Affect Age Apoptosis Biological Blood Blood Circulation Cancer Patient Cell Survival Cells Cessation of life Complex Contracts Coupled Development Disease Disseminated Malignant Neoplasm Dose Dose-Rate Drug Kinetics Drug or chemical Tissue Distribution Early Diagnosis Emulsions Functional RNA Gene Expression Goals Heart Human Immune response In Vitro Injection of therapeutic agent Kidney Kinetics Lead Liver Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate MicroRNAs Modification Molecular Mus Neoplasm Metastasis Oligonucleotides Oncogenes Patients Pharmacologic Substance Phase Phase I Clinical Trials Plasma Positioning Attribute Preparation Primates Process Property RNA Research Risk Risk Assessment Rodent Safety Scientist Series Specificity Tail Technology Testing Therapeutic Time Toxic effect Transgenic Mice Translations Tumor Suppressor Proteins Validation Variant Veins base cancer cell chemical substitution clinically relevant cost design improved in vivo mimetics mortality mouse model nonhuman primate nuclease nucleotide analog phase 1 study programs public health relevance safety study stability testing therapeutic development tumor tumor growth tumor progression tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Experimental evidence accumulated in the past few years indicates that several miRNAs likely function as tumor suppressors and that the altered expression of these miRNAs likely contributes to a significant number of human cancers. Mirna Therapeutics has identified approximately ten tumor suppressor miRNAs and is in the process of developing mimetics for two of these that will be subjected to efficacy and safety studies using advanced rodent and primate studies. These studies will ultimately be used to support an IND submission to the FDA for one or more miRNA-based therapies for the treatment of cancer patients. The focus of our proposed Phase I research is to use nucleotide analogs to improve the stabilities and activities of mimetics of two miRNAs that have proven to have therapeutic activities in mouse models of several different cancers. The goal for Phase I of the project is to create mimetics that are as much as ten-fold more effective than our current unmodified mimetics in inhibiting tumor growth in mice. Modified mimetics developed during Phase I will support our Phase II effort wherein the mimetics will be coupled with delivery agents developed in a parallel program. The mimetic/delivery combinations will be evaluated for therapeutic activities and pharmacokinetics using mouse models. The Specific Aims for our Phase I research are: (1) Develop modified mimetics with favorable stabilities and equivalent activities to unmodified mimetics and (2) Verify that the modified mimetics have therapeutic activities and target specificities that are equivalent to the unmodified miRNA mimetics that we have used for our efficacy studies to date. PUBLIC HEALTH RELEVANCE: Statement of Clinical Relevance Targeted therapies have the potential to revolutionize the treatment of cancer patients. A number of naturally occurring microRNAs, a newly discovered class of genetically-encoded RNA molecules, appear to function as powerful tumor suppressors in humans. We are developing synthetic versions of two of the more powerful tumor suppressor miRNAs to create therapies that can be used to inhibit the progression of cancer.

描述（由申请人提供）：过去几年中积累的实验证据表明，几种miRNA可能起抑制肿瘤的作用，并且这些miRNA的表达改变可能会导致大量的人类癌症。 miRNA Therapeutics已确定了大约十种肿瘤抑制器miRNA，并正在为其中两种的模拟物开发模拟物，它们将使用先进的啮齿动物和灵长类动物研究进行疗效和安全性研究。这些研究最终将用于支持一种或多种基于miRNA的疗法以治疗癌症患者的IND提交。我们提出的I期研究的重点是使用核苷酸类似物来改善两种miRNA的模拟物的稳定性和活性，这些miRNA被证明在几种不同癌症的小鼠模型中具有治疗活性。该项目的第一阶段的目标是创建模拟物在抑制小鼠肿瘤生长方面比目前未修饰的模拟物高出十倍。在第一阶段开发的修改模拟物将支持我们的II期努力，其中模拟物将与并行程序中开发的递送剂相结合。使用小鼠模型，将评估模拟/递送组合的治疗活动和药代动力学。我们第一阶段研究的具体目的是：（1）开发具有良好稳定性和等效活性的修改的模拟物，可用于未经修饰的模拟物，（2）验证修改后的模拟物具有治疗活动和靶向特异性，这些活动与未经修改的miRNA模拟物相当，我们用于我们的效率研究，以使我们的效率研究约会。公共卫生相关性：临床相关性靶向疗法的说明有可能彻底改变癌症患者的治疗。许多天然存在的microRNA，是一类新发现的遗传编码的RNA分子，似乎是人类中强大的肿瘤抑制剂。我们正在开发两个更强大的肿瘤抑制剂miRNA的合成版本，以创建可用于抑制癌症进展的疗法。