Research Core (Deverman)

摘要-资源核心 朊病毒病是由朊病毒蛋白（PrP）引起的一种致命的、不可治愈的神经退行性疾病。PrP， 由染色体基因PRNP编码并在所有哺乳动物中普遍表达， 但当它错误折叠成一种“朊病毒”时，就会引起疾病，这种朊病毒能够在构象上腐蚀其他病毒。 PrP分子。目标，团结所有武器的这一建议，是开发一种单剂量，永久性降低PrP 基因疗法治疗、预防或延缓朊病毒病。我们的多学科团队结合了领导力， 致力于患者科学家，朊病毒生物学家和首席PI Sonia Vallabh，拥有有关 到大卫刘组的基础编辑，乔纳森韦斯曼实验室的表观基因组编辑，以及交付 矢量工程和制造从本Deverman实验室，这将作为矢量核心。 贯穿这一建议的所有领域的是对能够显著增强CNS的载体的需要 在人类患者以及临床前模型中为这种全脑疾病进行基因递送。这种需求使得 关键的是整合新的突破，在交付载体工程以及专业知识，在载体 生物学、生产、质量控制和表征。通过其他正在进行的、资金充足的项目， Deverman实验室已经设计了改进的CNS递送载体，并建立了一个平台， 系统地鉴定具有与基因治疗相关的多种性状的其它载体。这项建议会 将这些正在进行的项目中的顶级候选人应用于降低PrP基因疗法的开发。的 由Deverman博士领导的矢量工程资源核心将进行工艺开发，生产， 制剂和递送载体的表征，以支持本研究中所有三个项目的体内研究。 建议;协助组织处理和生物分布分析;开发可扩展的生产和分析 管道，并为大规模制造提供技术转让和监督。在这一总体背景下， 根据该提案，资源核心将支持通过单一的- 剂量治疗，并提供了一个基本的概念验证的应用工程交付 在成人患者中系统施用CNS基因治疗的载体。

ABSTRACT — RESOURCE CORE Prion disease is a fatal, untreatable neurodegenerative disease caused by the prion protein (PrP). PrP, encoded by the chromosomal gene PRNP and expressed ubiquitously in all mammals, is not pathogenic in its native state, but causes disease when it misfolds into a "prion" capable of conformationally corrupting other PrP molecules. The goal, uniting all arms of this proposal, is to develop a single-dose, permanent PrP-lowering gene therapy to treat, prevent, or delay prion disease. Our multi-disciplinary team combines the leadership of committed patient-scientist, prion biologist and lead PI Sonia Vallabh with the cutting-edge expertise pertaining to base editing from the David Liu Group, epigenome editing from the Jonathan Weissman Lab, and delivery vector engineering and manufacturing from the Ben Deverman Lab, which will serve as the Vector Core. Cross-cutting all areas of this proposal is the need for vectors that can achieve dramatically enhanced CNS gene delivery for this whole brain disease in human patients as well as preclinical models. This need makes critical the integration of new breakthroughs in delivery vector engineering as well as expertise in vector biology, production, quality control, and characterization. Through other ongoing, fully funded projects, the Deverman lab has engineered improved delivery vectors for the CNS and established a platform for systematically identifying additional vectors with multiple traits relevant to gene therapy. This proposal will apply the top candidates from these ongoing projects to the development of a PrP-lowering gene therapy. The Vector Engineering Resource Core led by Dr. Deverman will undertake process development, production, formulation, and characterization of delivery vectors in support of the in vivo studies for all three projects in this proposal; assist with tissue handling and biodistribution analysis; develop a scalable production and analytical pipeline, and provide technology transfer and oversight for at-scale manufacturing. In the context of this overall proposal, the Resource Core will underpin the core goal of transforming prion disease therapy with a single- dose therapy, and also provide a foundational proof-of-concept for the application of engineered delivery vectors toward systemically-administered CNS gene therapy in adult human patients.