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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（由申请人提供）：幼年神经性Ceroid Lipofuscinosis （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的发病年龄在5-10岁之间，伴有进行性视力丧失、癫痫发作、认知和运动能力下降，并在青少年晚期至20岁出头死亡。目前还没有治疗JNCL的方法，这强调了寻找新的治疗方法来改善患有这种致命疾病的儿童的寿命和生活质量的重要性。我们实验室最近的研究表明，早期JNCL中异常的胶质细胞激活可能导致神经元丢失。特别是CLN3？ex7/8小胶质细胞可以产生许多已知具有神经毒性作用的促炎介质，而野生型（WT）细胞则没有反应。星形胶质细胞半通道（HC）的开放也在CLN3？Ex7/8小鼠，它允许分子从细胞内到细胞外环境的非歧视性通道和生理梯度的破坏。在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脑代谢组，导致最终导致神经元丢失的病理事件链。我们的假设是，用两类影响多种途径的化合物靶向异常胶质细胞激活将显著延缓JNCL的进展。第一种是ni -0602，是一种新型HC抑制剂，可减少谷氨酸在CLN3？ex7/8小鼠降至典型WT动物水平。另一组包括第二代磷酸二酯酶-4 （PDE4）抑制剂罗氟米司特和PDE4亚型特异性抑制剂，由辉瑞公司提供，可减弱CLN3？Ex7/8小胶质细胞也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抑制剂都可以减少包括AD和HD在内的许多疾病的炎症和神经元损失。该R21提案将通过评估ni -0602和PDE4抑制剂对CLN3？ex7/8老鼠。我们将建立每种药物的最佳剂量-反应谱，干预的理想治疗窗口，以及INI-0602和PDE4抑制剂是否在联合治疗方法中显示附加效应。i -0602和PDE4抑制剂作为延迟JNCL进展的新疗法的临床前评估将在以下具体目标中进行：1)半通道抑制剂i -0602可减轻早期JNCL中谷氨酸的积累，导致丘脑皮质结构中显著的神经元保留；2) PDE4抑制剂通过减少促炎介质的释放和谷氨酸的积累来减少JNCL中的神经元损失；3) i -0602与PDE4抑制剂联合治疗，由于药物作用机制不同，在阻止JNCL进展方面具有优越的疗效。总之，我们新的化合物选择原理，支持INI-0602和PDE4抑制剂作为JNCL治疗药物的初步数据，以及这些化合物在JNCL中的现有知识产权，为本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）

Astrocytes and lysosomal storage diseases.

DOI：
10.1016/j.neuroscience.2015.05.061
发表时间：
2016-05-26
期刊：
Neuroscience
影响因子：
3.3
作者：
Rama Rao KV;Kielian T
通讯作者：
Kielian T

Evidence for aberrant astrocyte hemichannel activity in Juvenile Neuronal Ceroid Lipofuscinosis (JNCL).

DOI：
10.1371/journal.pone.0095023
发表时间：
2014
期刊：
PloS one
影响因子：
3.7
作者：
Burkovetskaya M;Karpuk N;Xiong J;Bosch M;Boska MD;Takeuchi H;Suzumura A;Kielian T
通讯作者：
Kielian T

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

DOI：
10.1002/ana.24815
发表时间：
2016-12
期刊：
ANNALS OF NEUROLOGY
影响因子：
11.2
作者：
Aldrich, Amy;Bosch, Megan E.;Fallet, Rachel;Odvody, Jessica;Burkovetskaya, Maria;Rao, Kakulavarapu V. Rama;Cooper, Jonathan D.;Drack, Arlene V.;Kielian, Tammy
通讯作者：
Kielian, Tammy

Moving towards effective therapeutic strategies for Neuronal Ceroid Lipofuscinosis.

DOI：
10.1186/s13023-016-0414-2
发表时间：
2016-04-16
期刊：
Orphanet journal of rare diseases
影响因子：
3.7
作者：
Geraets RD;Koh Sy;Hastings ML;Kielian T;Pearce DA;Weimer JM
通讯作者：
Weimer JM

Searching for novel biomarkers using a mouse model of CLN3-Batten disease.

DOI：
10.1371/journal.pone.0201470
发表时间：
2018
期刊：
PloS one
影响因子：
3.7
作者：
Timm D;Cain JT;Geraets RD;White KA;Koh SY;Kielian T;Pearce DA;Hastings ML;Weimer JM
通讯作者：
Weimer JM