Engineering a human neuroimmune specific viral vector from Zika virus

从寨卡病毒中工程化人类神经免疫特异性病毒载体

基本信息

批准号：
10727590
负责人：
Benjamin B Bartelle
金额：
$ 18.45万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-07 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10727590
关键词：
Address Alzheimer&apos s Disease Animal Model Anti-Inflammatory Agents Astrocytes Autophagocytosis Biomedical Engineering Blood - brain barrier anatomy Brain Cell Culture System Cell Culture Techniques Cell Line Cells Clinical Trials Degenerative Disorder Directed Molecular Evolution Disease Engineering Enzyme-Linked Immunosorbent Assay Evolution Gene Transduction Agent Genes Genome Stability Harvest Helper-Inducer T-Lymphocyte Human Human Biology Immune Immunosuppression Infection Inflammation Inflammatory Inflammatory Response Innate Immune Response Mediating Medical Medicine Mental Depression Methods Microglia Modeling NF-kappa B Natural regeneration Nature Neurodegenerative Disorders Neuroimmune Neuronal Differentiation Neurons Parkinson Disease Pathogenicity Pathologic Pathology Pathway interactions Pharmaceutical Preparations Property RNA RNA Stability Recombinants Research Resistance STAT1 gene Sampling Shapes Signal Pathway Source Structural Genes Technology Therapeutic Titrations Transduction Gene Tropism Vaccine Therapy Viral Viral Genome Viral Vector Virus Work ZIKA Zika Virus cell type clinical development clinically relevant gene therapy human embryonic stem cell immunoregulation inflammatory marker mutant neuroinflammation neuropsychiatric disorder novel strategies particle pleiotropism pre-clinical therapy preclinical development pressure programs small molecule suicide gene synthetic biology targeted treatment tool transcriptome sequencing transcriptomics vector virus tropism whole genome

项目摘要

PROJECT SUMMARY Inflammation has been implicated in nearly every neuropsychiatric and degenerative disease, yet neuroimmune cells remain nearly intractable by every available therapeutic strategy. Small molecule drugs consistently fail clinical trials, as neuroimmune signaling pathways have essential pleiotropic functions in neighboring cell types. Meanwhile cell type selective therapies remain elusive, as microglia, and other neuroimmune cells, are intrinsically resistant to gene therapy vectors. Overcoming these unique challenges demands a new approach to medicine, drawing from an unlikely source of neuroimmune specific bioactivity. In nature, the Zika virus (ZKV) infects microglia, suppresses inflammation, and stimulates autophagy so expertly that almost half of infections go unnoticed. If this bioactivity could be safely refined, it would offer relief for neurodegenerative disorders from Parkinson’s to Alzheimer's disease. Parsing therapeutic from pathogenic mechanisms of the ZKV genome presents much greater complexity than ever previously addressed, but recent advances make it possible. Recombinant ZKV vectors, already in use, provide starting material for synthetic biology, while new viral assisted and continuous evolution methods allow bioengineering at scales capable of reshaping whole genomes. We can harness ZKV’s microglia specific immunosuppressive mechanisms into therapies with potential beyond any current technology. This proposal presents the first steps along the path towards an entirely new kind of therapy for neurodegenerative disorders.

项目概要几乎所有神经精神疾病和退行性疾病都与炎症有关，然而，神经免疫细胞仍然几乎无法通过任何可用的治疗策略来治疗。分子药物在临床试验中屡屡失败，因为神经免疫信号通路至关重要同时，细胞类型选择性疗法仍然难以捉摸，因为小胶质细胞和其他神经免疫细胞本质上对基因治疗载体有抵抗力。克服这些独特的挑战需要一种新的医学方法，借鉴一种不太可能的方法神经免疫特异性生物活性的来源。在自然界中，寨卡病毒 (ZKV) 感染小胶质细胞、抑制炎症并刺激如果这种生物活性能够安全地发挥作用，那么自噬就会如此熟练，几乎一半的感染都会被忽视。经过改进，它可以缓解从帕金森氏症到阿尔茨海默氏症等神经退行性疾病。从 ZKV 基因组的致病机制中解析治疗方法具有更大的意义复杂性比以往任何时候都解决，但最近的进展使重组 ZKV 成为可能。已经投入使用的载体为合成生物学提供了起始材料，而新的病毒则辅助和连续进化方法使得生物工程能够重塑整个基因组。我们可以利用 ZKV 的小胶质细胞特异性免疫抑制机制进行治疗该提案提出了该道路上的第一步。一种针对神经退行性疾病的全新疗法。