Autophagon: an Autophagy-Functionalizing Gene Therapy Tool for Neurodegenerative Diseases

自噬：一种用于神经退行性疾病的自噬功能化基因治疗工具

基本信息

批准号：
10589751
负责人：
Abraam M. Yakoub
金额：
$ 10.89万
依托单位：
UNIVERSITY OF NORTH DAKOTA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-15 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10589751
关键词：
3-Dimensional Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease therapy Amyloid beta-Protein Animal Model Animals Arrhythmia Autophagocytosis Autophagosome Basic Science Brain Brain region Cause of Death Cell Aggregation Cells Chemicals Chimeric Proteins Clinical Trials Cognitive Cognitive deficits Dangerousness Degradation Pathway Dementia Deposition Development Disease Disease model Drug usage Dyskinetic syndrome Engineering Excision Exhibits Foundations Future Genes Genetic Glutamates Healthcare Hippocampus Human Impairment In Vitro Injections Knock-in Learning Licensing Memory impairment Motor Mus Mutation Names Nerve Degeneration Neurodegenerative Disorders Neurons Organoids Outcome Parkinson Disease Pathogenesis Pathogenicity Pathway interactions Patients Peptides Persons Pharmaceutical Preparations Pharmacotherapy Poly A Population Precision therapeutics Preclinical Testing Process Proteins Psychoses Specificity Substantia nigra structure Synapses Synthetic Genes Testing Therapeutic Therapeutic Effect Toxic effect Vesicle Viral Vector abeta accumulation alpha synuclein care burden delivery vehicle design drug candidate effective therapy enhanced green fluorescent protein gene therapy in vivo induced pluripotent stem cell innovation motor deficit mouse model mutant neuroinflammation neuron loss neuronal survival neurotoxicity novel phosphoneuroprotein 14 presenilin-1 prevent promoter protein aggregation receptor recruit reduce symptoms research clinical testing side effect targeted treatment therapeutic evaluation therapy development tool

项目摘要

Project Summary Neurodegenerative diseases, especially Alzheimer’s Disease (AD) and Parkinson’s Disease (PD), affect millions of people globally and represent a US major healthcare burden. AD is the world’s most common cause of dementia, and is the sixth leading cause of death in the US. PD is motor disabling condition that advances to cognitive deficits. Currently there exist no effective therapies for AD or PD; even some of the drugs used to ameliorate symptoms, such as in PD, cause serious long-term side effects that may be worse than the disease itself. In AD and PD, accumulation of Amyloid-β (Aβ) or α-Synuclein (α-Syn) and their subsequent aggregation, cause neuronal toxicity, including neuroinflammation, synaptic deficits and neurodegeneration, leading to cognitive or motor deficits. In this application, we conceive an innovative genetic tool (named Autophagon, or AFN) to be developed as a gene therapy that helps target toxic Aβ or α-Syn species to autophagy, an important degradative pathway that is usually impaired in AD and PD. AFN will feature a synthetic gene fragment to help sequester Aβ or α-Syn aggregates and deliver them to the autophagic vesicles for clearance from the neurons. Using viral vectors, we will deliver AFN to cells or to mouse brain via specific stereotaxic injections. First, we will test AFN in vitro using 2D and 3D (brain organoid) neuronal cultures derived from iPSCs harboring APP/PSEN1 or α-Syn mutations that drive Aβ or α-Syn aggregation, respectively, and assess the ability of AFN to suppress aggregate formation and neuronal toxicity. Second, we will use mouse models of AD (with a genetic knock-in of human APP mutations that cause Aβ aggregation) and PD (expressing aggregation-prone mutant human α-Syn) to test the therapeutic potential of AFN and its ability to prevent aggregate formation, neurodegeneration, and cognitive or motor deficits in vivo. If successful, the proposed project will have a major impact on the neurodegenerative diseases field, by developing an effective potential gene therapy for AD and PD, and set the foundation for the next steps of preclinical and clinical testing of this suggested therapy. It may also provide a proof-of-concept for therapy development for other neurodegenerative disorders associated with protein aggregation.

项目概要神经退行性疾病，尤其是阿尔茨海默病 (AD) 和帕金森病 (PD)，会影响 AD 是全球最常见的病因，是全球数百万人的主要医疗负担。痴呆症是美国第六大死亡原因，PD 是一种发展为运动障碍的疾病。目前尚无针对 AD 或 PD 的有效疗法；甚至还没有一些用于治疗的药物；改善症状，例如帕金森病，会导致严重的长期副作用，可能比疾病本身更严重在 AD 和 PD 中，β 淀粉样蛋白 (Aβ) 或 α-突触核蛋白 (α-Syn) 的积累及其随后的聚集，引起神经元毒性，包括神经炎症、突触缺陷和神经变性，导致在此应用中，我们构思了一种创新的遗传工具（称为 Autophagon，或 AFN）将被开发为一种基因疗法，帮助靶向有毒的 Aβ 或 α-Syn 物种进行自噬，这是一种 AD 和 AFN 中通常受损的重要降解途径将以合成基因为特征。帮助隔离 Aβ 或 α-Syn 聚集体并将其递送至自噬囊泡进行清除的片段使用病毒载体，我们将通过特定的立体定向将 AFN 递送至细胞或小鼠大脑。首先，我们将使用源自 2D 和 3D（脑类器官）的神经培养物在体外测试 AFN。携带 APP/PSEN1 或 α-Syn 突变的 iPSC 分别驱动 Aβ 或 α-Syn 聚集，并评估其次，我们将使用 AFN 抑制聚集体形成和神经毒性的能力。 AD（通过基因敲入人类 APP 突变导致 Aβ 聚集）和 PD（表达易于聚集的突变体人类 α-Syn）来测试 AFN 的治疗潜力及其预防能力如果成功，建议进行体内聚集形成、神经变性以及认知或运动缺陷。该项目将通过开发有效的潜力，对神经退行性疾病领域产生重大影响 AD和PD的基因治疗，并为下一步的临床前和临床测试奠定基础建议的疗法还可以为其他疗法的开发提供概念验证。与蛋白质聚集相关的神经退行性疾病。