Small Molecule Drug Discovery for CLN3 and CLN6 Disease

针对 CLN3 和 CLN6 疾病的小分子药物发现

基本信息

批准号：
10316674
负责人：
Paul Trippier
金额：
$ 54.04万
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：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10316674
关键词：
Affect Apoptosis Apoptotic Autophagocytosis BCL2 gene Behavior Blindness CLN3 gene CLN6 gene Cells Ceramides Cessation of life Chemicals Child Childhood Cognitive Data Death Rate Dementia Deterioration Development Disease Disease model Drug Kinetics Family Functional disorder Generations Goals Homeostasis Human Impaired cognition In Vitro Individual Induced pluripotent stem cell derived neurons Infant Inherited Knock-in Mouse Lead Libraries Link Live Birth Medical Memory Mitochondria Modeling Modification Motor Mus Mutation Nature Neurodegenerative Disorders Neuronal Ceroid-Lipofuscinosis Neurons Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phenotype Physiological Processes Process Production Property Proteins Reporting Seizures Severities Spielmeyer-Vogt Disease Structure Therapeutic Therapeutic Agents Tissues Toxic effect Transgenic Mice Transgenic Organisms Visual impairment base behavioral phenotyping cancer therapy cheminformatics cognitive function common symptom design disease phenotype disorder subtype drug discovery drug metabolism effective therapy experience improved in vivo induced pluripotent stem cell innovation lead optimization mitochondrial dysfunction mouse model nerve stem cell neurobehavioral neuron loss pharmacophore premature protective effect scaffold screening small molecule stem cell model synergism therapeutic development therapeutic target therapeutically effective

项目摘要

PROJECT SUMMARY/ABSTRACT CLN3 and CLN6 disease are subtypes of a wider family of pediatric neurodegenerative diseases called the Neuronal Ceroid Lipofuscinoses (NCLs) or Batten Disease. The NCLs affect approximately 6-8 children per 100,000 live births worldwide. Common symptoms of CLN3 and CLN6 disease include vision impairment which progresses to blindness, seizures which increase in severity, cognitive and motor decline progressing to dementia, and ultimately premature death. No cure or effective treatment for either CLN3 or CLN6 disease is known. The development of new disease-modifying agents to treat CLN3 and CLN6 disease is an urgent and unmet medical need. Common phenotypes that are shared between all NCLs include dysfunctional autophagy leading to accumulation of storage material, reduced expression of the anti-apoptotic protein Bcl-2 and increased ceramide production leading to apoptotic death of neurons, and dysfunctional mitochondria. Autophagy and apoptosis are physiological process that contribute to cellular homeostasis. Dysfunction of one, or in many cases, both processes, is phenotypic across many neurodegenerative diseases in addition to the NCLs. While targeting either process individually results in promising pharmacological effect, no small molecule has been identified that is capable of modulating both synergistically. While a multi-target approach has been used in cancer treatment for many years, it has only recently begun being applied to neurodegenerative diseases and has yet to be explored in CLN3 and CLN6 disease. Through a structure-based approach, we have identified a library of multi-functional compounds that fuse autophagy activation activity, anti-apoptotic Bcl-2 induction and decreased ceramide synthesis resulting in translational activity to protect human induced pluripotent stem cell (iPSC)-derived neurons from externally- induced and phenotype-induced apoptosis. Moreover, we have shown in our preliminary data that iPSCs obtained from CLN3 patients and derived to functional neurons recapitulate the aberrant autophagy, apoptosis and mitochondrial function phenotype of the disease, and that these phenotypes can be rescued by selected lead compounds. Further, we show proof-of-concept that our lead compounds rescue CLN3 disease phenotypic behavioral deficits in a transgenic CLN3 mouse model. The goal of this application is to optimize our proprietary library of neuroprotective compounds to further understand their minimum pharmacophore, confer ‘drug-like’ properties, identify and eliminate any potential toxicity, optimize drug metabolism and pharmacokinetic parameters, further credential their mechanism of action and demonstrate proof-of-concept protective activity in additional patient iPSC-derived neuron lines and CLN3 and CLN6 transgenic mice.

项目概要/摘要 CLN3 和 CLN6 疾病是更广泛的儿科神经退行性疾病家族的亚型，称为神经元蜡质脂褐质沉积症 (NCL) 或巴顿病 (Batten 病) 每个 NCL 影响大约 6-8 名儿童。全球有 100,000 名活产婴儿，CLN3 和 CLN6 疾病的常见症状包括视力障碍。进展为失明，癫痫发作严重程度增加，认知和运动能力下降进展为 CLN3 或 CLN6 疾病目前尚无治愈或有效的治疗方法。已知。开发新的疾病缓解剂来治疗 CLN3 和 CLN6 疾病是当务之急所有 NCL 共有的未满足的医疗需求包括功能失调的自噬。导致储存物质的积累，抗凋亡蛋白 Bcl-2 的表达减少，神经酰胺产量增加导致神经元凋亡和线粒体功能障碍。自噬和凋亡是有助于细胞稳态的生理过程。此外，其中一个或在许多情况下两个过程中的一个或多个过程在许多神经退行性疾病中具有表型虽然单独针对任一过程都会产生有希望的药理作用，但效果并不小。已鉴定出能够协同调节两者的多靶点方法。多年来一直用于癌症治疗，但最近才开始应用于神经退行性疾病，并且尚未在 CLN3 和 CLN6 疾病中进行探索。通过基于结构的方法，我们已经确定了一个多功能化合物库，融合自噬激活活性、抗凋亡 Bcl-2 诱导和神经酰胺合成减少，导致保护人类诱导多能干细胞 (iPSC) 衍生的神经元免受外部影响的翻译活性此外，我们在初步数据中表明，iPSC 可以诱导细胞凋亡。从 CLN3 患者获得并衍生为功能性神经元，重现了异常的自噬、细胞凋亡和疾病的线粒体功能表型，并且这些表型可以通过选择来挽救此外，我们还证明了我们的主要化合物可以拯救 CLN3 疾病。转基因 CLN3 小鼠模型的表型行为缺陷。该应用程序的目标是优化我们专有的神经保护库以获取更多化合物了解它们的最小药效基团，赋予“药物样”特性，识别并消除任何潜在的毒性，优化药物代谢和药代动力学参数，进一步证实其作用机制在其他患者 iPSC 衍生的神经元系中采取行动并展示概念验证保护活性 CLN3 和 CLN6 转基因小鼠。