Genetic profiling of SLE patients with impaired NET degradation.

NET 降解受损的 SLE 患者的基因分析。

• 批准号: 10010568
• 负责人: Tobias Fuchs
• 金额: $ 25.17万
• 依托单位: NEUTROLIS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10010568
• 关键词: Accounting; Acute; Acute Disease; Animal Model; Antigen-Antibody Complex; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Binding; Biological; Biological Markers; Chromatin; Chronic; Clinic; Clinical; Clinical Trials; DNA Sequence Alteration; Data; Development; Diagnosis; Disease; Disease Management; Drug Screening; Enzymes; Filament; Genes; Genetic Markers; Genetic Polymorphism; Goals; Half-Life; Human; Impairment; In Vitro; Inflammation; Inflammatory; Lupus; Mission; Molecular; Mus; Mutation; Nature; Pathogenesis; Pathologic; Patients; Pharmaceutical Preparations; Phase; Proteins; Research Proposals; Role; Sampling; Serological; Single Nucleotide Polymorphism; Small Business Innovation Research Grant; Stratification; Symptoms; Systemic Lupus Erythematosus; Testing; Time; Variant; companion diagnostics; enzyme replacement therapy; experimental study; expression vector; extracellular; genetic analysis; genetic profiling; improved; in vivo; innovation; knockout animal; lead candidate; loss of function; loss of function mutation; neutrophil; novel; organ injury; outcome forecast; patient stratification; prevent; programs; therapy development; tool

ABSTRACT Systemic Lupus Erythematous (SLE) is the most common form of lupus, accounting for approximately 70% of all lupus cases. Patients can present with a multitude of clinical manifestations and with a diverse range of serological biomarkers making diagnosis and therapy challenging. All current SLE therapies rely on immunosuppressive drugs for managing disease symptoms. Neutrolis’ founding team has deep understanding on the role of Neutrophil Extracellular Traps (NETs) in inflammatory and autoimmune conditions. NETs are extracellular lattices of intact chromatin filaments decorated with toxic proteins. We and others, have demonstrated that NETs bind autoantibodies and from pathological immune complexes in SLE. More recently, we could identify the molecular mechanism how NETs are degraded in vivo. At Neutrolis, we develop biologics that promote NET degradation and provide a non-immunosuppressive for the treatment of autoimmune and inflammatory diseases, including SLE. We have identified a lead candidate, a Chromatinase™ that eliminates the pathologic effects of NETs in animal models for acute diseases and SLE. In this research proposal, we aim to characterize genetic mutations that cause reduced NET degradation in SLE patients with the goal to identify and stratify patients who will benefit from the innovative Chromatinase™ therapy. Novel mutations will also be explored and tested from 100 samples of SLE patients. Results from this project will enable us to move forward to a SBIR Phase II, in which we will analyze additional 1,500 SLE patients to generate a comprehensive panel of genetic markers, which promotes the development of Chromatinase™ towards clinical trials. The collected and tested data will support Neutrolis clinical program for SLE and other autoimmune indications. Taken together, we at Neutrolis have the expertise, platform, innovation and capabilities to execute the proposed project successfully in a timely manner and when completed the product could be clinically important.

抽象的 全身性狼疮红斑（SLE）是狼疮的最常见形式，约占70％ 所有狼疮病例。患者可以出现多种临床表现，并具有潜水员的范围 血清学生物标志物提出诊断和治疗挑战。所有当前的SLE疗法都依赖 用于管理疾病症状的免疫抑制药物。中心洛利斯的创始团队有深刻的了解 关于中性粒细胞外陷阱（NET）在炎症和自身免疫性条件中的作用。网是 完整的染色质丝的细胞外晶格，装饰有有毒蛋白。我们和其他人有 证明网络结合自身抗体和SLE中的病理免疫复合物。最近， 我们可以确定分子机制如何在体内降解网。在中性粒子，我们开发了生物制剂 促进净降解并提供非免疫抑制作用，以治疗自身免疫和 炎症性疾病，包括SLE。我们已经确定了一个消除染色剂™的铅候选者™ 急性疾病和SLE的动物模型中网的病理影响。在这项研究建议中，我们的目标 表征遗传突变，导致SLE患者的净降解降低，以识别目标 并分层将受益于创新染色酶™治疗的患者。新型突变也将是 探索并从100个SLE患者样本中进行了测试。该项目的结果将使我们能够前进 到SBIR II期，我们将分析其他1,500名SLE患者以产生全面的面板 遗传标记，它促进了染色质酶™向临床试验的发展。收集的 经过测试的数据将支持SLE和其他自身免疫性适应症的中性临床计划。拍摄 中立的我们共同具有执行拟议项目的专业知识，平台，创新和能力 及时成功，完成产品后可能在临床上很重要。