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（由适用提供）：这项为期两年的建议的目的是测试基于microRNA的治疗的可行性，作为治疗稀有囊性肾脏疾病的新型策略。常染色体隐性囊性肾脏疾病包括常染色体隐性多囊性肾脏疾病（ARPKD），肾囊肿和糖尿病（RCAD）和肾植物（NPHP）。这些罕见的遗传疾病的特征是在人类ARPKD，RCAD和失明（NPHP）中突变儿童中的囊肿。尽管这些疾病的发生率很少1：20,000，但它们具有显着的临床重要性。 ARPKD和NPHP是婴儿和儿童终末期肾脏疾病的最常见原因。已经鉴定出在人ARPKD，RCAD和NPHP中突变的基因。但是，这些疾病没有特定而有效的疗法，目前尚无临床试验中的药物。因此，需要新的疗法。在过去的10年中，我们的实验室研究了常染色体隐性囊性肾脏疾病的分子发病机理。我们已经开发了在患有这些疾病的人类中突变的相同基因中携带突变的直系同源小鼠模型。突变小鼠的表型类似于受影响人类的表型，表明它们代表了出色的动物模型。对突变小鼠的分析有助于揭示人类疾病的发病机理，并揭示它们与公共途径有联系。特别是，在RCAD中突变的转录因子Hnf-1调节PKHD1的转录，该转录在ARPKD中突变，Glis2和NPHP3在肾植物中突变。在此途径中，纠正异常可能是囊性肾脏疾病的有效治疗方法。最近的研究已将microRNA（miRNA）确定为人类疾病中的潜在分子靶标。 miRNA是简短的非编码RNA，可通过抑制翻译或促进互补的信使RNA的裂解来调节转录后基因表达。在初步研究中，我们已经确定了几个miRNA家族，这些家族在HNF-1突变细胞中被过表达。 miRNA的序列与已知囊性疾病基因（例如PKD2和PKHD1）编码的mRNA互补。这些研究确定了miRNA在囊性肾脏疾病的发病机理中的新作用，并表明抑制miRNA可能是减少囊肿形成的有效策略。最近，已经开发了调节体内miRNA活性的有效方法。 Antagomirs是化学修饰的寡核苷酸，可以在肠胃外施用，并具体彻底地灭活靶miRNA。在此提案中，我们将使用miRNA微阵列分析来全面识别在ARPKD，RCAD和NPHP的直系同源小鼠模型中表达的绝对miRNA。接下来，我们将测试靶向过表达miRNA的Antagomirs是否会抑制囊肿的形成并改善突变小鼠中的肾功能。研究将提供重要的临床前数据，证明这种方法治疗这些罕见但临床上重要的遗传疾病的可行性，并且对治疗影响肾脏的其他罕见疾病也具有广泛的影响。公共卫生相关性：常染色体隐性囊性肾脏疾病是罕见的遗传疾病，可导致儿童肾衰竭。目前尚无具体治疗。该建议将测试使用基于microRNA的新技术治疗这些疾病的可行性。