Research Core (Deverman)

抽象资源核 PrP病是由PrP引起的一种致命的、无法治愈的神经退行性疾病。PRP， 由染色体基因prnp编码，在所有哺乳动物中普遍表达，在其 天然状态，但当它错误折叠成能够构象破坏另一种 PRP分子。我们的目标是联合这项提议的所有方面，开发一种单剂、永久性的降低PrP的方法 用来治疗、预防或延缓病毒病的基因疗法。我们的多学科团队结合了 致力于患者-科学家、普里恩生物学家和领导皮索尼娅·瓦拉布，拥有 以David Liu Group的编辑为基础，Jonathan Weissman实验室的表观基因组编辑和交付 来自Ben Deverman实验室的矢量工程和制造，该实验室将作为矢量核心。 贯穿本提案所有领域的是需要能够实现显著增强的CNS的载体 这种全脑疾病在人类患者中的基因传递以及临床前模型。这种需求使得 关键是将交付载体工程的新突破与载体专业知识相结合 生物学、生产、质量控制和表征。通过其他正在进行的、全额资助的项目， Deverman实验室为CNS设计了改进的交付载体，并为 系统地识别具有与基因治疗相关的多个特征的额外载体。这项提议将 将这些正在进行的项目中的最佳候选者应用于降低PrP的基因疗法的开发。这个 由Deverman博士领导的向量工程资源核心公司将承担工艺开发、生产、 为这三个项目的体内研究提供支持的递送载体的制定和表征 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 提议，资源核心将支持通过单一的- 剂量疗法，也为工程化递送的应用提供了基本的概念验证 成年人类患者系统应用中枢神经系统基因治疗的载体。

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.