The Use of Complement Inhibitors as therapeutic agents in AMD

使用补体抑制剂作为 AMD 的治疗剂

• 批准号: 7107398
• 负责人: Woodruff Emlen
• 金额: $ 17.51万
• 依托单位: TALIGEN THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7107398
• 关键词: aging; antibody; asthma; complement; complement inhibitors; complement pathway regulation; eye; inflammation; lead; lighting; model; motivation; vision

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is the leading cause of blindness for Americans 60 years of age and older. It is estimated that the prevalence of AMD in the US is as high as 9 million, with 1.8 million individuals already suffering severe loss of vision from advanced AMD. As the population ages, the prevalence of AMD will continue to grow. The loss of visual acuity seen in even milder cases of AMD has a major impact on the quality of life as well as causing a significant economic burden to society. Studies on the pathogenesis of AMD have indicated that inflammation is a fundamental component of the disease. Furthermore, recent genetic evidence has strongly implicated a polymorphism in the complement control protein factor H as a major risk factor for the disease. Thus, it has been proposed that inadequate control of complement-driven inflammation may be a major factor in disease pathogenesis and that manipulation of the complement system may provide novel and promising therapeutic approaches to the treatment of AMD. This SBIR proposal will examine the potential therapeutic benefit of inhibition of the alternative pathway of complement activation in a constant-light exposure animal model of AMD. Inhibition of complement activation will be attained with a monoclonal Ab to the factor B component of the alternative pathway which has been licensed by Taligen Therapeutics, Inc. Recent studies by Dr. Michael Holers, Chief Scientific Officer of Taligen, in collaboration other investigators have demonstrated a critical role for factor B in driving inflammation in animal models of a number of diseases including asthma, ischemia-reperfusion injury, immunologic renal disease, post traumatic brain and spinal cord injury. In collaboration with Drs. Baerbel Roher and Gary Gilkeson at MUSC, we have obtained preliminary data to show that this antibody has a protective effect and a murine model of AMD. The Specific Aims of this proposal are to extend our preliminary observations to examine the effects of treatment with anti-factor B on retinal function and histology in an albino rat constant-light exposure model of AMD. Successful demonstration of a protective effect of this antibody will lead the company to initiate a full pre-clinical program (efficacy in larger animals, toxicology and pharmacokinetics) of this the antibody as a therapeutic for human AMD.

描述（由申请人提供）：年龄相关性黄斑变性 (AMD) 是 60 岁及以上美国人失明的主要原因。据估计，美国AMD患病率高达900万，其中已有180万人因晚期AMD而严重失明。随着人口老龄化，AMD的患病率将持续增长。即使是较轻微的 AMD 病例也会出现视力丧失，对生活质量产生重大影响，并给社会造成重大经济负担。对 AMD 发病机制的研究表明，炎症是该疾病的基本组成部分。此外，最近的遗传证据强烈表明补体控制蛋白 H 因子的多态性是该疾病的主要危险因素。因此，有人提出，对补体驱动的炎症控制不充分可能是疾病发病机制的主要因素，并且补体系统的操纵可能为AMD的治疗提供新颖且有前途的治疗方法。 该 SBIR 提案将在 AMD 的恒定光照动物模型中研究抑制补体激活替代途径的潜在治疗益处。通过 Taligen Therapeutics, Inc. 许可的替代途径 B 因子成分的单克隆抗体可抑制补体激活。 Taligen 首席科学官 Michael Holers 博士与其他研究人员合作的最新研究表明B 因子在许多疾病的动物模型中驱动炎症中发挥着关键作用，包括哮喘、缺血再灌注损伤、免疫性肾病、创伤后脑和脊髓损伤。与博士合作。 MUSC的Baerbel Roher和Gary Gilkeson，我们已经获得初步数据表明这种抗体具有保护作用以及AMD的小鼠模型。该提案的具体目标是扩展我们的初步观察结果，以检查抗因子 B 治疗对 AMD 的白化大鼠恒定光暴露模型中视网膜功能和组织学的影响。成功证明该抗体的保护作用将导致该公司启动该抗体作为人类 AMD 治疗剂的完整临床前计划（在大型动物中的功效、毒理学和药代动力学）。