Intrinsic anti-angiogenic activity of siRNA

siRNA 的内在抗血管生成活性

• 批准号: 7926172
• 负责人: Jayakrishna Ambati
• 金额: $ 43.16万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2012-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7926172
• 关键词: 2-thiouridine; Accounting; Adaptor Signaling Protein; Adopted; Affect; Age related macular degeneration; Angiogenesis Modulating Agents; Apoptosis; Architecture; Ascaridil; Biology; Blindness; Blood Vessels; Breast; Cell Proliferation; Cell surface; Cells; Chemicals; Choroidal Neovascularization; Cleaved cell; Clinical Trials; Complex; Data; Development; Disease; Double Stranded RNA Virus; Double-Stranded RNA; Drug Delivery Systems; Elderly; Endothelial Cells; Epidemic; Exudative age-related macular degeneration; Eye; Fire - disasters; Gene Mutation; Genes; Genetic; Goals; Growth; Immune; Immune response; Immune system; Incidence; Individual; Infiltration; Inhibition of Cell Proliferation; Interferons; Interleukin-12; Investigation; Kinetics; Laser injury; Lasers; Lead; Length; Leukocytes; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mediator of activation protein; Medicine; Messenger RNA; Modeling; Modification; Molecular; Molecular Profiling; Mus; Mutation; Natural Immunity; Nature; Nobel Prize; Ophthalmology; Panthera leo; Pathway interactions; Patients; Pharmacogenetics; Phase II Clinical Trials; Positioning Attribute; Prevalence; Process; Property; Public Health; RNA; RNA Interference; RNA-Induced Silencing Complex; Retina; Role; Signal Pathway; Signal Transduction; Surface; System; Techniques; Testing; Therapeutic; Thrombospondin 1; Toxic effect; Transcript; United States; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Work; angiogenesis; chemokine; cost; design; efficacy testing; gene therapy; human DICER1 protein; human TLR3 protein; in vivo; insight; interest; mRNA Transcript Degradation; mouse model; neovascular; nonhuman primate; novel; novel strategies; pigment epithelium-derived factor; programs; public health relevance; receptor; response; thrombospondin 2; tool

DESCRIPTION (provided by applicant): The discovery of RNA interference (RNAi) and its potential to silence any gene of interest via the RNA-induced silencing complex (RISC) has revolutionized modern genetics and launched a new class of therapeutics termed short interfering RNA (siRNA). The first clinical trials of siRNA were initiated in patients with choroidal neovascularization (CNV) due to age-related macular degeneration (AMD), which is the leading cause of blindness among the elderly in industrialized world and afflicts more people in the United States than all cancers combined. In new and exciting recent work, we made the surprising discovery that siRNAs uniformly suppress experimental CNV in mice, independent of RNAi. We found that that siRNAs against non- mammalian genes, genes not expressed in the eye, or random sequences without homology to any known gene, all suppressed CNV, as did a modified siRNA incapable of RISC incorporation. This novel class effect was mediated via activation of toll like receptor-3 (TLR3) and its adaptor protein TRIF, and induction of interferon-3 and interleukin-12. Interestingly, siRNAs targeting vascular endothelial growth factor (VEGF)-A or its receptor VEGFR-1, which are in Phase II clinical trials, also suppressed CNV via TLR3 activation and not cognate transcript knockdown. We will test the hypothesis that both targeted and non-targeted siRNAs activate TLR3 by direct interaction and trigger a cellular program of vascular growth suppression. The specific aims of this proposal are to further define the interaction between siRNA and TLR3, determine the precise anti-angiogenic mechanisms of siRNA-induced CNV suppression in mice, and test the efficacy of non-targeted siRNA in a non-human primate model of CNV. These studies will provide clarifying insights into the mechanisms underlying unanticipated siRNA activities in vivo, define the molecular architecture governing this intersection of vascular biology and innate immunity, provide pharmacogenetic data that will enable personalized medicine in patients with TLR3 mutations, and propel the development of new, more affordable anti-angiogenic therapeutics for the public health epidemic that is AMD.Angiogenesis (the growth of abnormal blood vessels) is responsible for the majority of blindness in patients with age-related macular degeneration (AMD), which accounts for a lion's share of the annual $51 billion cost of blindness in the United States. The Nobel Prize winning discovery of RNA interference led to the development of short interfering RNA (siRNA) as a new class of targeted drugs, which were first launched in clinical trials in AMD. Public Health Relevance: Our surprising discovery that all siRNAs have intrinsic anti-angiogenic activity has immediate and profound implications both for ongoing clinical trials and for treating the estimated 500 million people with diseases driven by angiogenesis.

描述（由申请人提供）：发现RNA干扰（RNAi）及其通过RNA诱导的沉默络合物（RISC）沉默任何感兴趣的基因的潜力已彻底改变了现代遗传学，并推出了一种新的治疗学，称为简短干扰RNA（SIRNA）。 siRNA的首次临床试验是在与年龄相关的黄斑变性（AMD）引起的脉络膜新生血管化（CNV）的患者中开始的，这是工业化世界中老年人失明的主要原因，并且折磨于美国的癌症人数比所有癌症组合的人数都多。在新的令人兴奋的最近工作中，我们发现了一个令人惊讶的发现，即siRNA均匀地抑制了与RNAi无关的小鼠中的实验CNV。我们发现，针对非哺乳动物基因的siRNA，在眼睛中未表达的基因或与任何已知基因同源的随机序列都抑制了CNV，而RISC掺入的改良siRNA也是如此。这种新颖的类效应是通过激活Toll（例如受体-3（TLR3）及其衔接蛋白TRIF）的激活以及诱导Interferon-3和interleukin-12的介导的。有趣的是，在II期临床试验中靶向血管内皮生长因子（VEGF）-A或其受体VEGFR-1的siRNA也通过TLR3激活抑制了CNV，而不是同类转录本敲低。我们将检验以下假设：靶向和非靶向siRNA通过直接相互作用激活TLR3并触发血管生长抑制的细胞程序。该提案的具体目的是进一步定义siRNA和TLR3之间的相互作用，确定siRNA诱导的小鼠CNV抑制的精确抗血管生成机制，并测试非靶向siRNA在非人类CNV的非人类灵长类动物模型中的疗效。这些研究将提供对体内意外siRNA活性的机制的澄清见解，定义了管理血管生物学和先天免疫相交的分子体系结构，可提供药物遗传学数据，可为TLR3突变的患者提供个性化医学，并提高新的抗抗病性，并提供更高的抗抗病性。 （异常血管的生长）负责与年龄相关的黄斑变性（AMD）患者的大多数失明，该患者占美国每年51亿美元失明成本的占一部分。诺贝尔奖获得了RNA干扰的发现，导致短暂干扰RNA（siRNA）作为一种新的有针对性药物，该药物首次在AMD的临床试验中启动。 公共卫生相关性：我们令人惊讶的发现，所有siRNA具有内在的抗血管生成活性对正在进行的临床试验以及治疗估计有5亿人受血管生成造成的疾病的人具有直接而深远的影响。