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：
10888798
负责人：
Abraam M. Yakoub
金额：
$ 45.71万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10888798
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.

项目摘要神经退行性疾病，特别是阿尔茨海默氏病（AD）和帕金森氏病（PD），影响全球成千上万的人代表了美国的主要医疗保健负担。广告是世界上最常见的原因痴呆症，是美国第六大死亡原因。 PD是运动破坏状况认知缺陷。目前尚无对AD或PD的有效疗法；甚至有些药物曾经改善症状，例如在PD中，会导致严重的长期副作用，可能比该病更糟本身。在AD和PD中，淀粉样蛋白β（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，导致认知或电机定义。在此应用中，我们携带一种创新的遗传工具（命名为Autophagon或 afn）将作为一种基因疗法开发，该基因疗法有助于靶向有毒Aβ或α-Syn种类自噬，一种重要的降级途径通常在AD和PD中受到损害。 AFN将具有合成基因片段以帮助隔离Aβ或α-Syn聚集体并将其输送到自噬蔬菜中以清除来自神经元。使用病毒载体，我们将通过特定的立体定位将AFN传递到细胞或小鼠脑注射。首先，我们将使用2D和3D（脑器官）神经元培养物在体外测试AFN 携带APP/PSEN1或α-SYN突变的IPSC分别驱动Aβ或α-Syn聚集的IPSC和评估 AFN抑制骨料形成和神经元毒性的能力。其次，我们将使用鼠标模型 AD（具有引起Aβ聚集的人类应用突变的遗传敲击）和PD（表达容易产生聚集的突变体人α-syn）测试AFN的治疗潜力及其预防能力体内的骨料形成，神经退行性变形，认知或运动防御性。如果成功，提议项目将通过开发有效的潜力来对神经退行性疾病领域产生重大影响 AD和PD的基因疗法，并为临床前和临床测试的下一步奠定了基础建议的治疗。它也可能为其他与蛋白质聚集有关的神经退行性疾病。