Engineering a human neuroimmune specific viral vector from Zika virus

项目总结 几乎每一种神经精神疾病和退行性疾病都与炎症有关， 然而，通过所有可用的治疗策略，神经免疫细胞仍然几乎难以治愈。小的 分子药物一直未能通过临床试验，因为神经免疫信号通路是必不可少的 在相邻的细胞类型中具有多效性。与此同时，细胞类型的选择性治疗仍然难以捉摸， 因为小胶质细胞和其他神经免疫细胞对基因治疗载体具有内在的抵抗力。 克服这些独特的挑战需要一种新的医学方法，从一种不太可能的 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，刺激 自噬如此熟练，以至于几乎一半的感染都没有被注意到。如果这种生物活动可以安全地 经过改进，它将缓解从帕金森氏症到阿尔茨海默病等神经退行性疾病。 从zkv基因组的致病机制解析治疗作用要大得多。 复杂性比以往任何时候都要高，但最近的进展使其成为可能。重组ZKV 已经在使用的载体为合成生物学提供了起始材料，而新的病毒辅助和 持续进化的方法使生物工程能够在规模上重塑整个基因组。 我们可以利用zkv的小胶质细胞特有的免疫抑制机制进行治疗 超越任何现有技术的潜力。这份提案提出了这条道路上的第一步 走向一种治疗神经退行性疾病的全新疗法。

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.