Therapeutic targeting of aberrant glial function during Juvenile Batten Disease

幼年巴顿病期间异常神经胶质功能的治疗靶向

基本信息

批准号：
8660113
负责人：
Tammy L Kielian
金额：
$ 37.63万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
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：
2014-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8660113
关键词：
10 year old Adolescent Affect Age Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Animals Area Astrocytes Attenuated Behavior Behavioral Biological Process Blindness Brain Brain region CLN3 gene Cessation of life Child Childhood Chronic Clinical Trials Cognitive Corpus striatum structure Data Disease Disease Progression Dose Drug effect disorder Event Foundations Future Generations Glucose Glutamate Transporter Glutamates Hippocampus (Brain)Huntington Disease Impaired cognition Inborn Genetic Diseases Inflammation Inflammatory Inflammatory Response Intellectual Property Intervention Ions Laboratories Life Expectancy Longevity Lysosomal Storage Diseases Mediator of activation protein Microglia Motor Motor Seizures Multiple Sclerosis Mus Mutation Neurodegenerative Disorders Neuroglia Neuronal Ceroid-Lipofuscinosis Neurons Pathogenesis Pathway interactions Patients Peripheral Pharmaceutical Preparations Physiological Preclinical Testing Process Production Quality of life Regimen Rodent Model Seizures Solid Spielmeyer-Vogt Disease Spinal Cord Structure Symptoms Teenagers Therapeutic Toxic effect Treatment Protocols United States National Institutes of Health Work base cell type design extracellular gamma-Aminobutyric Acid gap junction channel improved inhibitor/antagonist mouse model neuroinflammation neuron loss neuronal survival neurotoxic novel novel strategies novel therapeutics painful neuropathy phosphodiesterase IV postnatal pre-clinical preclinical study premature prevent public health relevance response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is a lysosomal storage disease caused by an autosomal recessive mutation in the CLN3 gene. JNCL presents between 5-10 years of age, with progressive vision loss, seizures, cognitive and motor decline, and death by late teens-early 20s. There is no treatment for JNCL, which underscores the significance of identifying novel therapeutics to improve lifespan and quality-of-life for children suffering from this deadly disease. Recent work from our laboratory suggests that aberrant glial activation during early JNCL may contribute to neuronal loss. In particular, CLN3?ex7/8 microglia are primed to produce numerous proinflammatory mediators with known neurotoxic effects, whereas wild type (WT) cells are non-responsive. Astrocyte hemichannel (HC) opening is also enhanced in numerous brain regions of CLN3?ex7/8 mice, which allows the non-discriminant passage of molecules from the intra- to extracellular milieus and disruption of physiologic gradients. The combination of early HC opening and aberrant microglial activation in JNCL likely disrupts the brain metabolome, contributing to the pathological chain of events that culminates in neuronal loss. Our hypothesis is that targeting aberrant glial activation with two classes of compounds that affect multiple pathways will significantly delay JNCL progression. The first, INI-0602, is a novel HC inhibitor that reduces glutamate accumulation in CLN3?ex7/8 mice to levels typical of WT animals. The other group includes the second generation phosphodiesterase-4 (PDE4) inhibitors Roflumilast and PDE4 subtype specific inhibitors provided by Pfizer that attenuate proinflammatory mediator production by CLN3?ex7/8 microglia and also increase astrocyte glutamate transporter expression. Importantly, both INI-0602 and PDE4 inhibitors reduce inflammation and neuronal loss in numerous disorders, including AD and HD. This R21 proposal will identify the optimal neuroprotective regimens for INI-0602 and PDE4 inhibitors, by evaluating effects on the brain metabolome, behavior, and neuronal survival in CLN3?ex7/8 mice. We will establish optimal dose-response profiles for each drug, the ideal therapeutic window for intervention, and whether INI-0602 and PDE4 inhibitors display additive effects in a combinational therapy approach. The preclinical assessment of INI-0602 and PDE4 inhibitors as novel therapeutics to delay JNCL progression will be examined in the following specific aims: 1) The hemichannel inhibitor INI-0602 attenuates glutamate accumulation during early JNCL, leading to significant neuronal sparing in thalamocortical structures; 2) PDE4 inhibitors reduce neuronal loss in JNCL by attenuating proinflammatory mediator release and glutamate accumulation; and 3) A combinational therapy with INI-0602 and PDE4 inhibitor provides superior efficacy to impede JNCL progression due to distinct mechanisms of drug action. Together, our novel rationale for compound selection, supporting preliminary data for INI-0602 and PDE4 inhibitors as JNCL therapeutics, and existing intellectual property for these compounds in JNCL, form a solid foundation for the preclinical testing outlined in this R21 application.

描述（由申请人提供）：少年神经蛋白脂肪促脂肪促脂肪促（JNCL）是一种由CLN3基因的常染色体隐性突变引起的溶酶体储存疾病。 JNCL介绍了5-10岁的年龄，具有渐进的视力丧失，癫痫发作，认知和运动衰落以及青少年20多岁的死亡。没有针对JNCL的治疗方法，它突显了鉴定新的治疗剂以改善这种致命疾病儿童的寿命和生活质量的重要性。我们实验室的最新工作表明，JNCL早期期间的异常神经胶质激活可能导致神经元丧失。尤其是，CLN3？ex7/8小胶质细胞被启动以产生许多具有已知神经毒性作用的促炎性介质，而野生型（WT）细胞无反应。在CLN3？ex7/8小鼠的许多大脑区域，星形胶质细胞半通道（HC）开口也得到了增强，该小鼠允许分子从细胞内到细胞外环境和生理梯度的破坏。 JNCL中早期HC开口和异常小胶质细胞激活的组合可能破坏了脑代谢组，这有助于导致神经元丧失的事件的病理链。我们的假设是，用两类影响多种途径的化合物靶向异常的神经胶质激活将显着延迟JNCL进展。第一个是INI-0602，是一种新型的HC抑制剂，可将Cln3？ex7/8小鼠的谷氨酸积累降低到典型的WT动物的水平。另一组包括辉瑞（Pfizer）提供的第二代磷酸二酯酶4（PDE4）抑制剂Roflumilast和PDE4亚型特异性抑制剂，这些抑制剂可通过CLN3？EX7/8微胶质细胞降低促炎性介质的产生，并增加星形胶质腺转运蛋白转运蛋白的表达。重要的是，INI-0602和PDE4抑制剂都减少了包括AD和HD在内的许多疾病中的炎症和神经元丧失。该R21建议将通过评估CLN3？EX7/8小鼠对脑代谢组，行为和神经元存活的影响，确定INI-0602和PDE4抑制剂的最佳神经保护方案。我们将为每种药物建立最佳的剂量反应概况，理想的干预治疗窗口以及INI-0602和PDE4抑制剂是否在组合治疗方法中显示出添加效应。在以下具体目的中，将检查对INI-0602和PDE4抑制剂作为延迟JNCL进展的新型治疗剂的临床前评估：1）Hemichannel抑制剂INI-0602减弱JNCL早期的谷氨酸积累，从而导致丘脑皮层结构中的显着神经元释放性神经元释放。 2）PDE4抑制剂通过减少促炎介质释放和谷氨酸积累来减少JNCL中的神经元丧失； 3）与INI-0602和PDE4抑制剂的组合疗法具有较高的功效，从而阻碍了由于药物作用的不同机制而导致的JNCL进展。共同提供了我们的新型化合物选择理由，支持INI-0602和PDE4抑制剂作为JNCL疗法的初步数据，以及JNCL中这些化合物的现有知识产权，构成了此R21应用中概述的临床前测试的坚实基础。