LM11A-31 neuroprotective efficacy in an animal model of HIV

描述(申请人提供)：即使在引入联合抗逆转录病毒疗法后，艾滋病毒感染仍然存在于中枢神经系统(CNS)。随着艾滋病毒感染人口的老龄化，病毒的长期存在和相关的炎症支持了中枢神经系统疾病的日益流行。体外研究表明，神经元功能障碍是由神经元钙的不稳定引起的，随后出现树突状珠状、突起修剪和突触丢失的损伤。我们已经证明，新的p75神经营养素受体配体LM11A-31可以预防感染猫免疫缺陷病毒(FIV)的猫神经培养物或暴露于HIV病毒粒子、gp120或有毒巨噬细胞条件培养液的大鼠神经培养物中的神经功能障碍和损伤。正如在许多疾病模型中看到的那样，神经元p75在对艾滋病毒的反应中增加，从而提供了一个被疾病过程上调的治疗靶点。这种保护作用是在纳摩尔浓度下观察到的，部分原因是恢复了钙稳态，从而防止了导致神经元损伤的最初功能障碍。单独的研究表明，该化合物跨越血脑屏障，在脑室蓄积，在体外和体内高浓度下对小鼠和猫都没有不良影响。不良反应测试包括生理(体重、血细胞计数、尿液分析、血液化学、器官重量和组织学)和行为测量(热敏性、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有神经保护效果的报道。部分基于上述研究，LM11A-31已被批准进行第一阶段研究，用于治疗阿尔茨海默病。我们的体外结果和体内初步研究表明，LM11A-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。拟议的研究将使用艾滋病毒相关神经发病的FIV模型来检验这一假设，同时还将解决在艾滋病毒感染情况下拟议的化合物治疗用途的重要问题。这一自然感染模型已经针对治疗测试进行了优化，并概括了感染和中枢神经系统疾病的特征，这些特征对人类的传播具有重要意义。一个主要的终点将是FIV诱导的认知缺陷的逆转。其他终点将包括证明大脑中的炎症减轻，评估长期治疗的毒性/不良影响，以及评估对病毒滴度和疾病进展的影响。这些研究将初步确定LM11A-31的体内有效性和安全性，为后续旨在建立LM11A-31作为治疗艾滋病毒相关神经功能障碍的药物的研究做准备。

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.