p75NTR ligands for ALS therapy

肌萎缩侧索硬化症(ALS)是一种进行性、致残性和最终致命性疾病 神经肌肉疾病在退伍军人中的发病率增加，目前 现有的治疗方法只有名义上的效果。这项提案的总体目标是确定 P75神经营养素受体的小分子调节剂(P75NTR)是否会抑制 肌萎缩侧索硬化症的病理进展和改善预后。神经营养素介导的受损 P75NTR相关死亡机制的信号和激活被认为是 肌萎缩侧索硬化症病理的潜在驱动因素。此外，p75NTR在有高血压风险的运动神经元中表达上调。 肌萎缩侧索硬化症的损伤和死亡，以及受体胞外区的脱落，反映了 配体的参与和信号传递与疾病的进展相关。先前的研究采用 针对治疗靶向p75NTR的多肽配体和受体下调已产生 结果好坏参半，部分原因可能是多肽不稳定、剂量不足、缺乏靶向 参与和/或干扰p75NTR活性的积极方面。非肽类小分子 分子口服生物可利用的p75NTR配体已经被开发出来，可以抑制伤害 通过受体传递信号并促进生存途径。他们已经被发现有 几种神经退行性疾病对信号、病理和行为结局的积极影响 损伤模式，包括ALS细胞培养模型。我们假设LM11A-31，a P75NTR配体目前处于阿尔茨海默病第二阶段测试，将抑制启动和/或 肌萎缩侧索硬化症相关细胞死亡信号、病理、症状和死亡率的进展。我们会 测定LM11A-31对动物功能状态、体重和存活过程的影响 携带ALS诱发的SOD1G93A突变，检测：LM11A-31药代动力学； 对p75NTR蛋白分解过程、尿液排泄和与天然配体结合的影响；以及， 激活与死亡和生存相关的信号通路。除了经典的细胞凋亡 途径，我们将检查对坏死性死亡途径的影响，这可能与 这种疾病。第二个ALS小鼠模型，携带FUSR521C突变，已知有 神经营养信号的缺陷，将检查p75NTR的表达模式以及 LM11A-31对信号转导的影响我们预计LM11A-31的治疗将推迟发病 和/或SOD1G93A小鼠症状和死亡的进展，并将使大部分 在这些和FUS R521C小鼠中相关的有害信号。这些都是积极的结果 研究将支持p75NTR作为ALS的治疗靶点，并将促进对 ALS患者LM11A-31。此外，这些结果可能会增加对p75NTR作用的了解 在ALS中的作用及其与非凋亡性死亡机制的关系。

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.