Treatment of HCMV in transplant vascular scelrosis

HCMV治疗移植血管硬化

• 批准号: 6549865
• 负责人: JAMES B HICKS
• 金额: $ 9.68万
• 依托单位: VIROGENOMICS, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-20 至 2003-03-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6549865
• 关键词: Adenoviridae; antisense nucleic acid; antiviral agents; arteriosclerosis; biotechnology; biotherapeutic agent; cardiac myocytes; cell migration; cytokine receptors; cytomegalovirus; drug design /synthesis /production; fluorescent dye /probe; laboratory rat; microorganism disease chemotherapy; receptor expression; smooth muscle; transfection /expression vector

DESCRIPTION (provided by applicant): Transplant Vascular Sclerosis (TVS) is an accelerated form of arteriosclerosis that is responsible for significant number of cases of chronic rejection in solid organ transplantation procedures. The incidence of TVS is approximately 15% of patients per year, leading to a prevalence of up to 60% of patients surviving at least 5 years. Among the risk factors identified for chronic rejection through TVS is infection by human cytomegalovirus (H)(CMV), an endemic herpesvirus carried by more than 60% of the U.S. population. (H)CMV infection does not cause noticeable acute disease in healthy individuals, but is implicated in several forms of chronic vascular disease. Recent work by Virogenomics' founding scientists has shown the CMV infection of arterial, but not venous, smooth muscle cells (SMC) results in significant cellular migration in vitro. Migration is dependent of expression of a specific one of the four chemokine receptors encoded by either rodent or human CMV. Virogenomics is testing the hypothesis that blocking the expression or function of US28, the human (HCMV) form of the gene can reduce or eliminate TVS in HCMV infected transplant patients. In this Phase I application we propose to test the effect of antisense molecules on the expression of r33, the rat CMV version of the receptor, and furthermore, to test whether antisense treatment can block SMC migration in vitro. The Phase II goals will extend this antisense strategy into animal models for TVS and eventually to initiate a drug discovery program to identify small molecule blocking human US28 function, with the ultimate goal of developing human therapeutics for the viral component of TVS. PROPOSED COMMERCIAL APPLICATIONS: Successful completion of this Phase I project will lead directly into Phase II animal model studies to determine whether antisense interention at the cell surface receptor level can reduce the negative effects of CMV on transplant vascular sclerosis in vivo. The commercial application will either be an antisense drug candidate or a validated assay system that will make it possible to screen for small molecule drug candidates or antibodies that work through this mechanism.

描述（由申请人提供）：移植血管硬化症（TVS）是一种加速的动脉硬化形式，是导致大量固体器官移植程序中大量慢性排斥反应病例的原因。电视的发病率约为每年15％的患者，导致多达60％的患者至少有5年的患者。在通过TVS慢性排斥的危险因素中，人类巨细胞病毒（H）（CMV）感染，这是美国60％以上美国人群携带的特有疱疹病毒。 （H）CMV感染不会引起健康个体的明显急性疾病，而是与几种形式的慢性血管疾病有关。病毒基因学创始科学家的最新工作表明，动脉，但没有静脉平滑肌细胞（SMC）的CMV感染导致体外细胞迁移显着。迁移取决于由啮齿动物或人CMV编码的四个趋化因子受体之一的表达。病毒组学检验了以下假设：阻止US28的表达或功能，该基因的人类（HCMV）形式可以减少或消除HCMV感染的移植患者中的TVS。在此阶段I应用中，我们建议测试反义分子对R33的表达的影响，R33，受体的大鼠CMV版本，以及测试反义治疗是否可以在体外阻止SMC迁移。第二阶段的目标将将这种反义策略扩展到电视的动物模型中，并最终启动一项药物发现计划，以识别阻断人类US28功能的小分子，其最终目标是为电视的病毒组件开发人类疗法。 拟议的商业应用： 该阶段I项目的成功完成将直接导致II期动物模型研究，以确定在细胞表面受体水平上的反义相互作用是否可以减少CMV对体内移植血管硬化症的负面影响。商业应用要么是反义药物的候选药物，也将是经过验证的测定系统，该系统将有可能筛选通过该机制起作用的小分子候选药物或抗体。