NOVEL THERAPY FOR RESISTANT FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS)

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。原发性局灶节段性肾小球硬化（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，也没有经过证实的治疗方法。针对这一紧急情况，美国国立卫生研究院资助的一项国家多中心随机临床试验正在进行中，以比较环孢素（目前的标准护理）与MMF和口服地塞米松脉冲联合治疗类固醇耐药FSGS患者的疗效。预计将有相当数量的患者因先前接受过其中一种试验疗法的治疗而不符合这项试验的资格，或者对实验治疗没有反应。迫切需要开发新的治疗方法来治疗这些难治性患者。有两种方法来解决这个问题——免疫治疗或抗纤维化治疗来延缓疾病的进展。在缺乏明确的治疗靶点和候选治疗方法的情况下，本提案将评估三种新型药物的安全性和有效性，这些药物可能具有减少耐药FSGS患者肾纤维化和减缓疾病恶化速度的能力。阶段性创新奖的申请由两个不同的部分组成。在R21期的初始阶段，将测试两种新疗法（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期，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R21/R33项目建立的基础设施应该证明对未来将出现的其他新疗法的有效评估是有用的。

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.