IRE1 alpha inhibitors for Retinal Degenerative Diseases

IRE1 α 抑制剂治疗视网膜退行性疾病

基本信息

批准号：
9184941
负责人：
Bradley J Backes
金额：
$ 7.32万
依托单位：
OPTIKIRA, LLC
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2017-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9184941
关键词：
Acute Affect American Aniline Animal Model Apoptosis Attenuated Benchmarking Biological Assay Blindness Cell Death Cell Survival Cells Cessation of life Chronic Clinical Cytoprotection Defect Development Dimensions Disease Electroretinography Endoplasmic Reticulum Endoribonucleases Engineering Genes Genetic Models Goals Health Histology Human Inflammation Inherited Injection of therapeutic agent Lead Link Measures Mediating Messenger RNA Molecular Genetics Mus Mutation OmpR protein Optical Coherence Tomography Pathogenesis Patients Permeability Phase Phosphotransferases Photoreceptors Prevention Proteins RNA Splicing Retina Retinal Retinal Degeneration Retinal Diseases Retinitis Pigmentosa Rhodopsin Ribonucleases Risk Rodent Rodent Model Series Severities Signal Pathway Signal Transduction Solubility Sterility Stress Suicide Testing Therapeutic Tunicamycin Urea Vertebrate Photoreceptors Vision Vitreous humor Work analog base cell suicide design endoplasmic reticulum stress glycosylation improved in vivo Model inhibitor/antagonist kinase inhibitor mRNA Transcript Degradation mouse model novel novel strategies novel therapeutic intervention novel therapeutics premature programs protein folding response response biomarker small molecule transcription factor

项目摘要

DESCRIPTION (provided by applicant): Approximately 100,000 Americans suffer from vision loss due to Retinitis Pigmentosa (RP). Despite significant progress in elucidating the molecular genetics of RP over the past three decades, no disease-modifying therapies have been approved. There is compelling evidence implicating endoplasmic reticulum (ER) stress in the pathogenesis of various forms of RP, especially those caused by autosomal dominant protein-folding mutations in Rhodopsin (ADRP). Our team has uncovered key mechanisms whereby the unfolded protein response (UPR), an intracellular signaling pathway activated by ER stress, promotes either cell survival or cell death depending on the severity of the stress. Dominantly inherited Rhodopsin mutations generate high/chronic ER stress to promote photoreceptor cell loss and blindness. We have identified IRE1α as the master unfolded protein response regulator that determines cell fate under ER stress, and have demonstrated that IRE1α inhibitors we call KIRAs (Kinase Inhibitor RNase Attenuators) provide functional cytoprotection to ER stress-challenged photoreceptors. We propose to optimize KIRAs for intravitreal administration and determine photoreceptor cytoprotection efficacy in an acute in vivo model of ER-stress-driven retinal degeneration. This work represents early steps towards developing a new class of agents for RP with disease- modifying potential. The specific Aims of this proposal are: 1: To improve the profile of KIRAs for intraocular administration and efficacy; and, 2: To demonstrate optimized KIRAs boost efficacy in an ER stress model of rodent RP.

描述（由申请人提供）：大约 100,000 名美国人因色素性视网膜炎 (RP) 而遭受视力丧失，尽管在过去三十年中在阐明 RP 的分子遗传学方面取得了重大进展，但尚未批准任何令人信服的疾病缓解疗法。有证据表明内质网（ER）应激在各种形式的 RP 发病机制中，尤其是由常染色体显性蛋白折叠突变引起的 RP视紫红质 (ADRP)。我们的团队发现了未折叠蛋白反应 (UPR)（一种由内质网应激激活的细胞内信号通路）的关键机制，根据显性遗传性视紫红质突变的严重程度，可促进细胞存活或死亡。 /慢性内质网应激促进感光细胞损失和失明我们已经确定 IRE1α 是决定内质网应激下细胞命运的主要未折叠蛋白反应调节因子，并证明了 IRE1α。我们称之为 KIRA（激酶抑制剂 RNase 衰减剂）的抑制剂可为 ER 应激挑战的光感受器提供功能性细胞保护。我们建议优化 KIRA 的玻璃体内给药，并确定 ER 应激驱动的视网膜变性的急性体内模型中的光感受器细胞保护功效。代表了开发具有疾病缓解潜力的新型 RP 药物的早期步骤。制定该提案的具体目标是： 1：改善 KIRA 的眼内给药特性和功效；2：证明优化的 KIRA 在啮齿动物 RP 的 ER 应激模型中增强功效。