p75NTR ligands for ALS therapy

用于 ALS 治疗的 p75NTR 配体

• 批准号: 9974285
• 负责人: STEPHEN M. MASSA
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9974285
• 关键词: ALS patients; Address; Adult; Affect; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animals; Apoptotic; Area; Astrocytes; Binding; Bioavailable; Brain-Derived Neurotrophic Factor; Cause of Death; Cell Culture Techniques; Cell Death; Cell Death Signaling Process; Cell Survival; Cells; Central Nervous System Diseases; Cessation of life; Characteristics; Clinical; Clinical Treatment; Clinical Trials; Development; Disease; Disease Outcome; Disease Progression; Dose; Drug Kinetics; Effectiveness; Excretory function; Exhibits; Extracellular Domain; Genetically Engineered Mouse; Goals; Histopathology; Human; Impairment; In Vitro; Incidence; Inflammation; Inflammatory; Injury; Knowledge; Ligands; Maintenance; Measures; Mediating; Modeling; Motor; Motor Neurons; Mus; Mutant Strains Mice; Mutation; NGFR Protein; Nerve Cell Survival; Nerve Degeneration; Nerve Growth Factor Receptors; Nerve Growth Factors; Neurites; Neuroglia; Neurologic; Neuromuscular Diseases; Oral; Pathology; Pathway interactions; Pattern; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Positioning Attribute; Proteins; Proteolysis; Proteolytic Processing; Proto-Oncogene Proteins c-akt; Receptor Down-Regulation; Regulation; Reporting; Riluzole; Risk; Role; Serum; Signal Pathway; Signal Transduction; Spinal Cord; Symptoms; Testing; Therapeutic; Therapeutic Agents; Therapeutic Trials; Tissues; Vertebral column; Veterans; Weight; Work; behavioral outcome; blood-brain barrier penetration; cell injury; clinical development; effective therapy; experimental study; functional status; improved outcome; in vivo; insight; interest; member; mortality; mouse model; mutant; mutant mouse model; neuron loss; neurotrophic factor; novel therapeutics; phase 2 testing; pre-clinical; receptor; research clinical testing; response; small molecule; sortilin; superoxide dismutase 1; symptomatic improvement; therapeutic target; urinary

Amyotrophic lateral sclerosis (ALS) is a progressive, disabling and ultimately fatal neuromuscular disease which has increased incidence in veterans and upon which currently available therapies have only nominal effects. The overall goal of this proposal is to determine whether a small molecule modulator of the p75 neurotrophin receptor (p75NTR) will inhibit progression of pathology and improve outcomes in ALS. Impaired neurotrophin-mediated signaling and activation of p75NTR-associated death mechanisms have been implicated as potential drivers of ALS pathology. Moreover, p75NTR is upregulated in motor neurons at risk for injury and death in ALS, and shedding of the extracellular domain of the receptor, a reflection of ligand engagement and signaling, correlates with disease progression. Prior studies employing peptide ligands and receptor down-regulation to therapeutically target p75NTR have yielded mixed results, perhaps in part due peptide instability, inadequate dosing, lack of target engagement, and/or interference with positive aspects of p75NTR activity. Non-peptide small molecule orally-bioavailable p75NTR ligands have been developed that can inhibit injurious signaling and promote survival pathways via the receptor. They have been found to have positive effects on signaling, pathology and behavioral outcomes in several neurodegenerative and injury paradigms, including ALS cell culture models. We hypothesize that LM11A-31, a p75NTR ligand currently in phase II testing for Alzheimer’s disease, will inhibit the initiation and/or progression of ALS-associated cell death signaling, pathology, symptoms and mortality. We will determine LM11A-31 effects on the course of functional status, weight and survival in animals carrying the ALS-inducing SOD1G93A mutation, and examine: LM11A-31 pharmacokinetics; effects on p75NTR proteolytic processing, urinary excretion and binding to its native ligands; and, activation of death and survival-related signaling pathways. In addition to classical apoptotic pathways, we will examine effects on necroptotic death pathways which may be associated with the disease. A second ALS mouse model, bearing the FUSR521C mutation and known to have deficits in neurotrophic signaling, will be examined for p75NTR expression patterns as well as effects of LM11A-31 on signaling. We expect that treatment with LM11A-31 will delay onset and/or progression of symptoms and death in the SOD1G93A mice, and will normalize much of the associated deleterious signaling in those and FUS R521C mice. Positive results of these studies would support p75NTR as a therapeutic target in ALS, and would facilitate testing of LM11A-31 in ALS patients. Further, these results could add to knowledge of the role of p75NTR in ALS and its relationship to non-apoptotic death mechanisms.

肌萎缩侧索硬化症（ALS）是一种进行性、致残性和最终致命的疾病， 神经肌肉疾病在退伍军人中的发病率增加，目前 现有的治疗方法仅具有名义上的效果。本提案的总体目标是确定 p75神经营养因子受体（p75 NTR）的小分子调节剂是否会抑制 病理学进展并改善ALS的结局。神经营养素介导的受损 p75 NTR相关的死亡机制的信号传导和激活已经被牵连， ALS病理学的潜在驱动因素。此外，p75 NTR在运动神经元中上调， ALS中的损伤和死亡，以及受体胞外结构域的脱落，反映了 配体接合和信号传导与疾病进展相关。先前的研究采用 肽配体和受体下调到治疗靶点p75 NTR已经产生了 混合结果，可能部分由于肽不稳定、剂量不足、缺乏靶点 参与和/或干扰p75 NTR活性的积极方面。非肽小 已经开发了分子口服生物可利用的p75 NTR配体，其可以抑制有害的 信号传导并通过受体促进生存途径。他们被发现 对几种神经退行性疾病的信号传导、病理学和行为结果的积极影响 和损伤范例，包括ALS细胞培养模型。我们假设LM 11 A-31， p75 NTR配体目前在阿尔茨海默病的II期试验中，将抑制阿尔茨海默病的起始和/或 ALS相关细胞死亡信号传导、病理学、症状和死亡率的进展。我们将 确定LM 11 A-31对动物功能状态、体重和存活过程的影响 携带ALS诱导的SOD 1G 93 A突变，并检测：LM 11 A-31药代动力学; 对p75 NTR蛋白水解加工、尿排泄和与其天然配体结合的影响;以及， 死亡和生存相关信号通路的激活。除了经典的凋亡 途径，我们将研究对坏死性死亡途径的影响，这可能与 这种疾病第二种ALS小鼠模型，携带FUSR 521 C突变，已知具有 神经营养信号的缺陷，将检查p75 NTR表达模式以及 LM 11 A-31对信号传导的影响。我们希望用LM 11 A-31治疗可以延迟发病， 和/或SOD 1G 93 A小鼠中症状和死亡的进展，并且将使大部分 这些小鼠和FUS R521 C小鼠中的相关有害信号。这些积极成果 研究将支持p75 NTR作为ALS的治疗靶点，并将有助于检测 ALS患者中的LM 11 A-31。此外，这些结果可以增加对p75 NTR作用的认识。 及其与非凋亡性死亡机制的关系。