LM11A-31 neuroprotective efficacy in an animal model of HIV

LM11A-31 在 HIV 动物模型中的神经保护功效

基本信息

批准号：
8789501
负责人：
RICK B MEEKER
金额：
$ 39.2万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8789501
关键词：
Address Adverse effects Aftercare Age Aging Alzheimer&apos s Disease Animal Model Animals Antibodies Apoptotic Appearance Astrocytes Attention Behavioral Blood - brain barrier anatomy Blood Chemical Analysis Body Weight Brain CD8B1 gene Calcium Cell Count Cell Density Cells Central Nervous System Diseases Chronic Clinic Clinical Cognition Disorders Cognitive Cognitive deficits Complete Blood Count Conditioned Culture Media Data Dendrites Development Disease Disease Progression Disease model Evaluation Evaluation Indexes Exploratory Behavior Family Felidae Feline Immunodeficiency Virus Felis catus Foundations Functional disorder Glial Fibrillary Acidic Protein Goals HIV HIV Envelope Protein gp120 HIV Infections Histology Homeostasis Human Huntington Disease Immune Impaired cognition In Vitro Individual Infection Inflammation Kinetics Ligand Binding Ligands Lymphocyte Subset Measures Mediating Microglia Modeling Mononuclear Motor Mus NGFR Protein Nerve Degeneration Nervous system structure Neuraxis Neurologic Neuronal Dysfunction Neurons Neuropathogenesis Organ Weight Outcome Pathogenesis Pathology Patients Performance Peripheral Blood Mononuclear Cell Phase I Clinical Trials Physiological Plasma Population Preparation Prevalence Process Rattus Reporting Research Design Safety Satellite Viruses Sensory Sensory Thresholds Severities Signal Pathway Spinal cord injury Staging Structure Synapses Systemic disease T-Lymphocyte Temporal Lobe Testing Therapeutic Therapeutic Uses Toxic effect Toxin Translations Traumatic Brain Injury Treatment Efficacy Urinalysis Viral Viral Load result Virion Virus Virus Diseases Virus Replication antiretroviral therapy base behavior measurement drug candidate effective intervention frontal lobe gait examination immunopathology in vivo macrophage morphometry nervous system disorder neuroprotection neurotrophic factor novel phase 1 study prevent protective effect public health relevance relating to nervous system response restoration therapeutic target transcriptional coactivator p75

Address Adverse effects Aftercare Age Aging Alzheimer&apos s Disease Animal Model Animals Antibodies Apoptotic Appearance Astrocytes Attention Behavioral Blood - brain barrier anatomy Blood Chemical Analysis Body Weight Brain CD8B1 gene Calcium Cell Count Cell Density Cells Central Nervous System Diseases Chronic Clinic Clinical Cognition Disorders Cognitive Cognitive deficits Complete Blood Count Conditioned Culture Media Data Dendrites Development Disease Disease Progression Disease model Evaluation Evaluation Indexes Exploratory Behavior Family Felidae Feline Immunodeficiency Virus Felis catus Foundations Functional disorder Glial Fibrillary Acidic Protein Goals HIV HIV Envelope Protein gp120 HIV Infections Histology Homeostasis Human Huntington Disease Immune Impaired cognition In Vitro Individual Infection Inflammation Kinetics Ligand Binding Ligands Lymphocyte Subset Measures Mediating Microglia Modeling Mononuclear Motor Mus NGFR Protein Nerve Degeneration Nervous system structure Neuraxis Neurologic Neuronal Dysfunction Neurons Neuropathogenesis Organ Weight Outcome Pathogenesis Pathology Patients Performance Peripheral Blood Mononuclear Cell Phase I Clinical Trials Physiological Plasma Population Preparation Prevalence Process Rattus Reporting Research Design Safety Satellite Viruses Sensory Sensory Thresholds Severities Signal Pathway Spinal cord injury Staging Structure Synapses Systemic disease T-Lymphocyte Temporal Lobe Testing Therapeutic Therapeutic Uses Toxic effect Toxin Translations Traumatic Brain Injury Treatment Efficacy Urinalysis Viral Viral Load result Virion Virus Virus Diseases Virus Replication antiretroviral therapy base behavior measurement drug candidate effective intervention frontal lobe gait examination immunopathology in vivo macrophage morphometry nervous system disorder neuroprotection neurotrophic factor novel phase 1 study prevent protective effect public health relevance relating to nervous system response restoration therapeutic target transcriptional coactivator p75

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项目摘要

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.

描述（由申请人提供）：即使在引入抗逆转录病毒疗法的联合疗法之后，中枢神经系统（CNS）仍然存在HIV感染。随着HIV感染的人群年龄，病毒和相关炎症的长期存在和相关炎症支持CNS疾病的越来越多。体外研究表明，神经元功能障碍是由神经元钙的不稳定触发的，然后以树突状珠子的形式出现损伤，过程修剪和突触丧失。我们已经证明，在感染了猫免疫缺陷病毒（FIV）或大鼠神经培养物感染的猫神经培养物中，新型的p75神经营养蛋白受体配体LM11A-31可防止神经功能障碍和损害，暴露于HIV VIRIONS，GP120或毒性乳腺癌条件。从许多疾病模型中可以看出，神经元p75响应于HIV，从而提供了一个被疾病过程上调的治疗靶标。保护作用是在纳摩尔浓度下观察到的，部分原因是恢复钙稳态，从而防止了导致神经元损伤的初始功能障碍。单独的研究表明，该化合物越过了脑部室中积累的血脑屏障，并且在小鼠和猫的体外和体内都没有不良反应。对不良反应的测试包括生理（体重，CBC，尿液分析，血液化学，器官重量和组织学）和行为措施（热敏感性，步态分析，兽医检查）。在衰老，阿尔茨海默氏病，亨廷顿疾病，脊髓损伤和创伤性脑损伤的动物模型中，神经保护功效也有报道。 LM11A-31的一部分基于上述研究，已被批准用于I阶段的开发研究，以治疗阿尔茨海默氏病。我们的体外结果和体内研究的初步研究表明，LM11A-31也将是保护神经系统免受HIV相关损害的有效干预措施。拟议的研究将使用与HIV相关的神经病发生的FIV模型测试这一假设，同时还解决了在HIV感染中对化合物提出的治疗使用重要的问题。这种自然感染模型已被优化，用于治疗测试，并概括了感染的特征和CNS疾病对于转化为人类的特征。主要终点将是FIV引起的认知缺陷的逆转。其他终点将包括表明大脑炎症减少，评估毒性/不良反应，并长期治疗以及对病毒滴度和疾病进展的影响的评估。这些研究将建立LM11A-31的初始体内功效和安全性，以准备旨在建立LM11A-31的随后研究，以作为HIV相关神经功能障碍的治疗方法。