Novel TLR3 inhibitors for geographic atrophy of age-related macular degeneration

新型 TLR3 抑制剂治疗年龄相关性黄斑变性地图状萎缩

• 批准号: 7892963
• 负责人: Jayakrishna Ambati
• 金额: $ 18.38万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7892963
• 关键词: Accounting; Affect; Age related macular degeneration; American; Americas; Apoptosis; Apoptotic; Biological Assay; Blindness; Blood Vessels; Candidate Disease Gene; Cell Culture Techniques; Cell Death; Cell Survival; Cells; Cessation of life; Chemical Structure; Choroid; Choroidal Neovascularization; Clinical Trials; Collaborations; Data; Dimerization; Double-Stranded RNA; Economics; Endothelial Cells; Epidemic; Eye; FDA approved; Fluorescein Angiography; Foundations; Fundus photography; Genes; Genetic Polymorphism; Goals; Histology; Human; Immune; Interferons; Interleukin-12; Knowledge; Laboratories; Lead; Length; Link; Measures; Mediating; Medical; Molecular; Molecular Models; Mus; Nature; Nucleotides; Ophthalmology; Panthera leo; Pathogenesis; Patients; Pharmaceutical Chemistry; Phosphorylation; Photoreceptors; Physiological; Prevalence; RNA Binding; RNA Interference; RNA Interference Pathway; Reporting; Retina; Retinal; Retinal Degeneration; Risk; Structure of retinal pigment epithelium; Therapeutic; United States; Vision; Work; Yang; aging population; base; caspase-3; cost; geographic atrophy; human TLR3 protein; improved; in vivo; inhibitor/antagonist; molecular modeling; monomer; novel; prevent; public health relevance; sensor; trafficking; transmission process

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) affects some 10 million people in the United States. Blindness in AMD occurs due to either choroidal neovascularization (CNV) or geographic atrophy (GA). Whereas new treatments for CNV offer the prospect of vision improvement, the nebulous understanding of GA pathogenesis has precluded the arrival of any FDA-approved therapy for the nearly 1 million Americans that have GA. In a multi-center collaboration, we recently reported that a hypomorphic polymorphism in toll-like receptor-3 (TLR3), an innate immune sensor of double stranded RNA (dsRNA), conferred protection from GA, making it the first candidate gene specific for GA. We showed that TLR3 activation by long dsRNA induced apoptotic cell death of primary human retinal pigmented epithelium (RPE) cells and choroidal endothelial cells (CECs) and retinal degeneration in mice resembling GA, thereby establishing a functional link between TLR3 and GA. New and exciting recent work from my laboratory revealed the presence of non-physiological long dsRNA in the eyes of patients with GA but not in human eyes without AMD. Thus we hypothesize that TLR3 activation by long dsRNA triggers retinal and choroidal cell death and promotes GA. Using molecular modeling we discovered a novel class of ultrashort (us)-dsRNAs that function as TLR3 inhibitors in vivo. The objective of this proposal is to identify the optimal us-dsRNA molecules that can rescue TLR3-mediated retinal degeneration to achieve our long-term goal of advancing them as therapeutics for GA. These proof-of-concept studies will form the basis for an R01 application that will define the detailed mechanisms of action of long dsRNA and us-dsRNA. Successful completion of this project also will have the high translational impact of laying the foundation for a collaborative clinical trial for GA, which is presently an unmet medical need. PUBLIC HEALTH RELEVANCE: Geographic atrophy is responsible for 10% of blindness due to age-related macular degeneration (AMD). There is no FDA-approved therapy for the 1 million Americans with GA. Our recent discovery of TLR3 as the first gene specifically associated with GA and our exciting new finding that double stranded RNA (dsRNA), which activates TLR3, is present in human eyes with GA support the pursuit of a novel class of TLR3 inhibitors that we have discovered as potential therapeutics for this unmet medical need.

描述（由申请人提供）：与年龄相关的黄斑变性（AMD）在美国影响约1000万人。 AMD的失明是由于脉络膜新生血管形成（CNV）或地理萎缩（GA）引起的。尽管对CNV的新疗法提供了改善视力的前景，但对GA发病机理的模糊理解排除了对拥有GA的近100万美国人的任何FDA批准疗法的到来。在多中心的合作中，我们最近报道说，Toll样受体3（TLR3）中的型多态多态性，这是一种固有的双滞留RNA（DSRNA）的先天免疫传感器（DSRNA），从GA提供了保护，使其成为GA的第一个候选基因。我们表明，长dsRNA诱导类似于GA的小鼠的原代人视网膜色素上皮（RPE）细胞和脉络膜内皮细胞（CEC）和视网膜变性的TLR3激活，从而建立了TLR3和GA之间的功能性联系。我实验室的最新工作揭示了GA患者眼中存在非生理长的DSRNA，但在没有AMD的人眼中没有。因此，我们假设长dsRNA激活TLR3会触发视网膜和脉络膜细胞死亡，并促进GA。使用分子建模，我们发现了一种新型的超用作（US）-DSRNA，可作为TLR3抑制剂在体内发挥作用。该提案的目的是确定可以营救TLR3介导的视网膜变性的最佳US-DSRNA分子，以实现我们将其作为GA治疗的长期目标。这些概念验证研究将构成R01应用的基础，该应用将定义长dsRNA和US-DSRNA的详细作用机理。该项目的成功完成还将产生高转化的影响，即为GA的协作临床试验奠定基础，GA目前是未满足的医疗需求。 公共卫生相关性：由于年龄相关的黄斑变性（AMD），地理萎缩造成了10％的失明。对于具有GA的100万美国人，没有FDA批准的疗法。我们最近将TLR3作为与GA相关的第一个基因以及激活TLR3的双链RNA（DSRNA）的令人兴奋的新发现存在于人眼中，GA支持了追求一种新颖的TLR3抑制剂，我们发现我们作为这种无效医疗需求的潜在治疗方法。