NOVEL THERAPY FOR RESISTANT FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS)

抵抗性局灶节段性肾小球硬化症 (FSGS) 的新疗法

• 批准号: 7377133
• 负责人: HOWARD TRACHTMAN
• 金额: $ 1.09万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7377133
• 关键词: NOVEL; THERAPY; RESISTANT; FOCAL; SEGMENTAL

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Primary Focal Segmental Glomerulosclerosis (FSGS) is a serious renal disease, accounting for nearly 10-15% of all pediatric and adult patients requiring chronic dialysis or transplantation. Not only is the incidence of this disease rising, especially in select ethnic groups such as Blacks and Hispanics, the etiology of FSGS remains obscure and there is no proven therapy. In response to this urgent situation, a national multicenter NIH-funded randomized clinical trial is underway to compare the efficacy of cyclosporine, the current standard of care, with a combination of MMF and oral dexamethasone pulses in patients with steroid-resistant FSGS. It is anticipated that a significant number of patients will be ineligible for this trial because of prior treatment with one of the test therapies or will fail to respond to the experimental treatment. There is a pressing need to develop novel therapies to treat these refractory patients. There are two approaches to this problem - immunotherapy or antifibrotic therapy to retard disease progression. In the absence of a well-defined therapeutic target and a candidate treatment, this proposal will evaluate the safety and efficacy of three novel agents that may have the capacity to reduce renal fibrosis and slow the rate of deterioration of disease in patients with resistant FSGS. The Phased Innovation Award application is composed of two distinct portions. During the initial stage, the R21 Phase, the safety, tolerance, and pharmacokinetic profile of two novel therapies - a TNF-a antagonist and a PPARg agonist -- will be tested. In the second stage, the R33 phase, a hybrid ranking and selection Phase II study will be performed to assess the efficacy of these two treatments and an anti-TGF-b antibody compared to optimal conservative medical therapy. The outcome of this study will guide the design of a formal Phase III randomized clinical trial. The infrastructure that is established for the performance of this R21/R33 project should prove useful for the efficient assessment of additional novel therapies that will to arise in the future.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。原发性局灶节段性肾小球硬化症 (FSGS) 是一种严重的肾脏疾病，占所有需要慢性透析或移植的儿童和成人患者的近 10-15%。这种疾病的发病率不仅在上升，特别是在黑人和西班牙裔等特定种族群体中，而且 FSGS 的病因仍然不清楚，并且没有经过验证的治疗方法。为了应对这一紧急情况，一项由 NIH 资助的全国多中心随机临床试验正在进行，以比较当前标准治疗环孢菌素与 MMF 和口服地塞米松脉冲联合治疗对类固醇耐药 FSGS 患者的疗效。预计大量患者由于先前接受过一种测试疗法的治疗而没有资格参加该试验，或者对实验性治疗没有反应。迫切需要开发新疗法来治疗这些难治性患者。有两种方法可以解决这个问题——免疫疗法或抗纤维化疗法来延缓疾病进展。在缺乏明确的治疗靶点和候选治疗的情况下，该提案将评估三种新药的安全性和有效性，这些新药可能能够减少耐药 FSGS 患者的肾纤维化并减缓疾病恶化的速度。阶段性创新奖申请由两个不同的部分组成。在初始阶段，即 R21 阶段，将测试两种新型疗法（TNF-a 拮抗剂和 PPARg 激动剂）的安全性、耐受性和药代动力学特征。在第二阶段，即 R33 阶段，将进行混合排名和选择 II 期研究，以评估这两种治疗方法和抗 TGF-b 抗体与最佳保守药物治疗相比的疗效。这项研究的结果将指导正式的 III 期随机临床试验的设计。为实施 R21/R33 项目而建立的基础设施应该有助于有效评估未来将出现的其他新疗法。