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PKD1 derepression as a potential therapy for Polycystic Kidney Disease

PKD1 去抑制作为多囊肾病的潜在治疗方法

基本信息

批准号：
10693402
负责人：
Vishal Patel
金额：
$ 54.57万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10693402
关键词：
Ablation Address Adult Affect Alleles Attenuated Autosomal Dominant Polycystic Kidney Base Sequence Binding Cells Chemicals Chronic Clinical Research Cyclic AMP Cyst Disease Disease model Drug Targeting End stage renal failure Epigenetic Process Epithelial cyst Evolution Exhibits FRAP1 gene Gene Dosage Genetic Genetic Diseases Germ-Line Mutation Goals Growth Human In Vitro Individual Inflammation Inherited Mediating Messenger RNA Metabolism MicroRNAs Modeling Modification Mus Mutate Mutation Names Oligonucleotides PKD1 gene Pathogenicity Pathway interactions Patients Persons Pharmaceutical Preparations Phase Ib Trial Polycystic Kidney Diseases Prevalence Proprotein Convertase 1 Publishing Repression Safety Testing Therapeutic Treatment Efficacy Tubular formation Untranslated Regions Variant Work c-myc Genes clinical investigation derepression design dosage early onset feasibility testing human disease human model improved mRNA Translation mouse model novel novel therapeutics pre-clinical prevent programs tolvaptan transcriptomics urinary

项目摘要

Abstract Autosomal dominant polycystic kidney disease (ADPKD) is amongst the most common monogenetic disorders, with an estimated prevalence of 12.5 million people worldwide. Unfortunately, >50% of ADPKD patients develop end-stage renal failure and treatment options are still limited. Recent studies point to reduced PKD1 gene dosage as the disease mechanism for many ADPKD patients. This revelation opens the door to an exciting possibility that reversing PKD1 decline may arrest ADPKD in these individuals. However, despite the transformative potential, no PKD1-targeting drugs are under clinical investigation. Our goal in this application is to provide a scientific roadmap for developing a novel PKD1-boosting therapeutic approach. We propose a novel idea that along with the germline mutation, inefficient translation of mRNAs produced by the non-inactivated PKD1 allele also contributes to the lower PKD1 dosage and aggravates ADPKD. This idea emanates from our preliminary studies, where we found that deleting the cis-inhibitory miR-17 motif from the PKD1 3’- UTR is sufficient to improve mRNA translation and to raise PC1 levels. In turn, this approach ameliorates cyst growth in mice and in vitro human ADPKD models. Based on these promising observations, we propose: (1) using genetic proof-of-principle approaches to study the impact of PKD1 derepression in ADPKD mouse and human models, and (2) test the feasibility of oligonucleotides that outcompete and prevent miR-17 from binding to PKD1 as novel therapeutics to raise PC1 levels.

摘要