LM11A-31 neuroprotective efficacy in an animal model of HIV

描述（由申请人提供）：即使在引入联合抗逆转录病毒疗法后，HIV感染仍持续存在于中枢神经系统（CNS）中。随着HIV感染人群的老龄化，病毒和相关炎症的慢性存在支持CNS疾病的患病率增加。体外研究表明，神经元功能障碍是由神经元钙的不稳定引发的，随后出现树突珠状、突起修剪和突触丢失形式的损伤。我们已经证明，新的p75神经营养因子受体配体，LM 11 A-31，防止神经功能障碍和损害，在猫神经培养感染猫免疫缺陷病毒（FIV）或大鼠神经培养暴露于HIV病毒粒子，gp 120或有毒的巨噬细胞条件培养基。正如在许多疾病模型中所看到的，神经元p75响应于HIV而增加，从而提供了由疾病过程上调的治疗靶点。在纳摩尔浓度下观察到保护作用，部分原因是恢复钙稳态，从而防止导致神经元损伤的初始功能障碍。单独的研究表明，该化合物穿过血脑屏障，在脑室中蓄积，在小鼠和猫的体外和体内高浓度下均无不良反应。不良反应试验包括生理学（体重、CBC、尿分析、血液化学、器官重量和组织学）和行为测量（热敏感性、步态分析、兽医检查）。在衰老、阿尔茨海默病、亨廷顿病、脊髓损伤和创伤性脑损伤的动物模型中也报道了神经保护功效。部分基于上述研究，LM 11 A-31已被批准用于开发阿尔茨海默病治疗的I期研究。我们的体外结果和初步的体内研究表明，LM 11 A-31也将是一种有效的干预措施，以保护神经系统免受艾滋病毒相关的损害。拟议的研究将使用HIV相关神经发病机制的FIV模型来测试这一假设，同时还解决了在HIV感染背景下该化合物的拟议治疗用途的重要问题。这种天然感染模型已被优化用于治疗测试，并概括了感染和CNS疾病的特征，这些特征对于转化为人类非常重要。一个主要终点将是FIV诱导的认知缺陷的逆转。其他终点将包括证明脑部炎症减少、评估长期治疗的毒性/不良反应以及评价对病毒滴度和疾病进展的影响。这些研究将建立LM 11 A-31的初始体内功效和安全性，为旨在建立LM 11 A-31作为HIV相关神经功能障碍的治疗的后续研究做准备。

DESCRIPTION (provided by applicant): Even after the introduction of combination antiretroviral therapies, HIV infection persists in the central nervous system (CNS). The chronic presence of virus and the associated inflammation supports an increasing prevalence of CNS disease as the HIV-infected population ages. In vitro studies have shown that neuronal dysfunction is triggered by a destabilization of neuronal calcium followed by the appearance of damage in the form of dendritic beading, pruning of processes and synapse loss. We have demonstrated that the novel p75 neurotrophin receptor ligand, LM11A-31, prevents the neural dysfunction and damage, in feline neural cultures infected with feline immunodeficiency virus (FIV) or rat neural cultures exposed to HIV virions, gp120 or toxic macrophage conditioned medium. As seen in many disease models, neuronal p75 increases in response to HIV, thereby providing a therapeutic target that is upregulated by the disease process. The protective effect was seen at nanomolar concentrations and was due, in part, to a restoration of calcium homeostasis, thereby preventing the initial dysfunction that leads to neuronal damage. Separate studies demonstrated that the compound crossed the blood-brain barrier, accumulated in the brain compartment and was free of adverse effects at high concentrations in vitro and in vivo in both mice and cats. Tests for adverse effects included physiological (body weight, CBC, urinalysis, blood chemistry, organ weights and histology) and behavioral measures (thermal sensitivity, gait analysis, veterinary examination). Neuroprotective efficacy has also been reported in animal models of aging, Alzheimer disease, Huntington disease, spinal cord injury and traumatic brain injury. Based in part on the above studies, LM11A-31 has been approved for Phase I studies for development as a treatment for Alzheimer disease. Our in vitro results and preliminary in vivo studies indicate that LM11A-31 will also be an effective intervention to protect the nervous system against HIV-associated damage. The proposed studies will test this assumption using the FIV model of HIV-associated neuropathogenesis while also addressing issues important for the proposed therapeutic use of the compound in the context of HIV infection. This natural infectious model has been optimized for therapeutic testing and recapitulates features of infection and CNS disease important for translation to humans. A major endpoint will be the reversal of FIV-induced cognitive deficits. Additional endpoints will include demonstration of reduced inflammation in the brain, assessment of toxicity/adverse effects with long-term treatment and evaluation of effects on virus titers and disease progression. These studies will establish initial in vivo efficacy and safety of LM11A-31 in preparation for subsequent studies designed to establish LM11A-31 as a treatment for HIV-associated neural dysfunction.