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：
8788453
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 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8788453
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 Health 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 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 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（申请人提供）：幼年神经元蜡质脂褐质沉积症（JNCL）是一种由 CLN3 基因常染色体隐性突变引起的溶酶体贮积病。 JNCL 发病年龄为 5-10 岁，伴有进行性视力丧失、癫痫发作、认知和运动能力下降，并在十几岁至 20 岁出头时死亡。 JNCL 尚无治疗方法，这凸显了寻找新疗法来延长患有这种致命疾病的儿童的寿命和生活质量的重要性。我们实验室最近的工作表明，早期 JNCL 期间神经胶质细胞的异常激活可能导致神经元损失。特别是，CLN3?ex7/8 小胶质细胞会产生大量具有已知神经毒性作用的促炎介质，而野生型 (WT) 细胞则无反应。 CLN3?ex7/8 小鼠的许多脑区的星形胶质细胞半通道 (HC) 开放也得到增强，这允许分子从细胞内环境到细胞外环境的无差别通道和生理梯度的破坏。 JNCL 中早期 HC 开放和异常小胶质细胞激活的结合可能会破坏大脑代谢组，从而导致最终导致神经元损失的病理事件链。我们的假设是，用两类影响多种途径的化合物来靶向异常的神经胶质细胞激活将显着延迟 JNCL 的进展。第一种是 INI-0602，是一种新型 HC 抑制剂，可将 CLN3?ex7/8 小鼠中的谷氨酸积累降低至 WT 动物的典型水平。另一组包括辉瑞公司提供的第二代磷酸二酯酶 4 (PDE4) 抑制剂罗氟司特和 PDE4 亚型特异性抑制剂，它们可减弱 CLN3?ex7/8 小胶质细胞产生的促炎介质，并增加星形胶质细胞谷氨酸转运蛋白的表达。重要的是，INI-0602 和 PDE4 抑制剂均可减少多种疾病（包括 AD 和 HD）中的炎症和神经元损失。该 R21 提案将通过评估对 CLN3?ex7/8 小鼠大脑代谢组、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剂量反应曲线、干预的理想治疗窗口，以及 INI-0602 和 PDE4 抑制剂在联合治疗方法中是否表现出相加效应。 INI-0602 和 PDE4 抑制剂作为延缓 JNCL 进展的新型疗法的临床前评估将在以下具体目标中进行检查：1）半通道抑制剂 INI-0602 减弱早期 JNCL 期间的谷氨酸积累，导致丘脑皮质结构中的神经元显着保留； 2) PDE4抑制剂通过减弱促炎介质释放和谷氨酸积累来减少JNCL中的神经元损失； 3) 由于不同的药物作用机制，INI-0602 和 PDE4 抑制剂的联合疗法可提供卓越的疗效，阻止 JNCL 进展。总之，我们对化合物选择的新颖原理、支持 INI-0602 和 PDE4 抑制剂作为 JNCL 治疗药物的初步数据以及 JNCL 中这些化合物的现有知识产权，为 R21 申请中概述的临床前测试奠定了坚实的基础。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Efficacy of phosphodiesterase-4 inhibitors in juvenile Batten disease (CLN3).

磷酸二酯酶 4 抑制剂对幼年巴顿病 (CLN3) 的疗效。

DOI：
发表时间：
2016-12
期刊：
影响因子：
11.2
作者：
Aldrich, Amy;Bosch, Megan E;Fallet, Rachel;Odvody, Jessica;Burkovetskaya, Maria;Rama Rao, Kakulavarapu V;Cooper, Jonathan D;Drack, Arlene V;Kielian, Tammy
通讯作者：
Kielian, Tammy

Astrocytes and lysosomal storage diseases.

星形胶质细胞和溶酶体贮积病。