MicroRNA-Based Therapeutics for Rare Cystic Kidney Diseases

基于 MicroRNA 的罕见囊性肾病治疗方法

基本信息

批准号：
7832043
负责人：
Peter Igarashi
金额：
$ 49.59万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-22 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7832043
关键词：
Adult Affect Animal Model Animals Autosomal Recessive Polycystic Kidney Binding Biological Process Blindness Cardiovascular Diseases Cells Child Clinical Clinical Data Clinical Trials Code Cyst Cystic Kidney Diseases Cystic kidney Development Diabetes Mellitus Disease End stage renal failure Family Fibrosis Functional RNA Gene Expression Genes Genetic Genetic Transcription Genomics Goals Hereditary Disease Human Incidence Individual Infant Kidney Kidney Diseases Kidney Failure Knockout Mice Laboratories Link Liquid substance Liver Fibrosis Malignant Neoplasms Messenger RNA Methods MicroRNAs Microarray Analysis Modeling Molecular Molecular Profiling Molecular Target Morbidity - disease rate Mus Mutant Strains Mice Mutate Mutation Nephronophthisis Newborn Infant Normal Range Oligonucleotides Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phenotype Plants Play Principal Investigator Proteins Rare Diseases Regulator Genes Renal function Role Sequence Analysis Staging Testing Therapeutic Tissues Transcript Translations Virus Diseases base effective therapy human disease improved in vivo mRNA Transcript Degradation mortality mouse model mutant nervous system disorder new technology novel novel strategies novel therapeutic intervention overexpression pre-clinical programs public health relevance restoration transcription factor

项目摘要

DESCRIPTION (provided by applicant): The goal of this two-year proposal is to test the feasibility of microRNA-based therapeutics as a novel strategy for the treatment of rare cystic kidney diseases. Autosomal recessive cystic kidney diseases include autosomal recessive polycystic kidney disease (ARPKD), renal cysts and diabetes (RCAD), and nephronophthisis (NPHP). These rare genetic disorders are characterized by the formation of cysts in the kidneys and progressive kidney failure. Extrarenal manifestations include congenital hepatic fibrosis (ARPKD), diabetes (RCAD), and blindness (NPHP). Although these disorders are rare with incidences of 1:20,000 or less, they have significant clinical importance. ARPKD and NPHP are the most common monogenic causes of end-stage kidney disease in infants and children. The genes that are mutated in human ARPKD, RCAD, and NPHP have been identified. However, no specific and effective therapies exist for these diseases, and no drugs are currently in clinical trials. Therefore, new therapeutic approaches are needed. For the past 10 years, our laboratory has investigated the molecular pathogenesis of autosomal recessive cystic kidney diseases. We have developed orthologous mouse models carrying mutations in the same genes that are mutated in humans with these disorders. The phenotypes of the mutant mice resemble the phenotypes of affected humans indicating that they represent excellent animal models. Analysis of the mutant mice has helped unravel the pathogenesis of the human diseases and revealed that they are linked in a common pathway. In particular, the transcription factor HNF-1¿, which is mutated in RCAD, regulates the transcription of PKHD1, which is mutated in ARPKD, and GLIS2 and NPHP3, which are mutated in nephronophthisis. Thus, correction of abnormalities in this pathway may be an effective therapeutic approach for cystic kidney diseases. Recent studies have identified microRNAs (miRNAs) as potential molecular targets in human diseases. miRNAs are short, non-coding RNAs that regulate post-transcriptional gene expression by inhibiting translation or promoting cleavage of complementary messenger RNAs. In preliminary studies, we have identified several families of miRNAs that are abnormally overexpressed in HNF-1¿ mutant cells. The sequences of the miRNAs are complementary to mRNAs encoded by known cystic disease genes, such as PKD2 and PKHD1. These studies identify a novel role of miRNAs in the pathogenesis of cystic kidney diseases and suggest that inhibition of miRNAs may be an effective strategy for reducing cyst formation. Recently, effective methods for modulating the activity of miRNAs in vivo have been developed. Antagomirs are chemically modified oligonucleotides that can be administered parenterally and that specifically and durably inactivate target miRNAs. In this proposal, we will use miRNA microarray analysis to comprehensively identify miRNAs that are abnormally expressed in orthologous mouse models of ARPKD, RCAD, and NPHP. Next, we will test whether the administration of antagomirs targeting the overexpressed miRNAs inhibit cyst formation and improve renal function in mutant mice. Such studies would provide important pre-clinical data demonstrating the feasibility of this approach for the treatment of these rare but clinically important genetic disorders and would also have broad implications for the treatment of other rare disorders affecting the kidney. PUBLIC HEALTH RELEVANCE: Autosomal recessive cystic kidney diseases are rare genetic disorders that produce kidney failure in children. No specific treatment currently exists. This proposal will test the feasibility of treating these disorders using a new technology, microRNA-based therapeutics.

描述（由申请人证明）：这是为了治疗稀有肾脏疾病（ARPKD）的策略所提供的基于microRNA的盛宴。，这些罕见的遗传疾病肾脏和肾脏肾脏衰竭包括先天性肝纤维化（ARPKD），糖尿病（RCAD）和失明（NPHP）。在婴儿和儿童中，最常见的末期肾脏肾脏疾病的原因。临床试验。优秀的动物模型。在RCAD中静音，在ARPKD中柔和的PKHD1的转录，GLIS2和NPHP3因此，在该途径中的异常校正可能会发现研究中的microRNA（miRNA）是人类疾病中的潜在分子靶标通过抑制翻译或促进Clementary Messenger RNA。突变细胞由已知的Cystem疾病基因编码，例如PKD2和PKHD1。化学修饰的寡核苷酸。临床前证明了治疗稀有但临床上重要的基因的可行性A。ND也将对其他影响肾脏的其他罕见罕见疾病具有广泛的影响。公共卫生的相关性：常染色体遗传性肾脏肾脏是罕见的遗传疾病，可以通过使用microRNA-bassed来测试这一建议。