Research Core (Deverman)

研究核心（德弗曼）

• 批准号: 10669493
• 负责人: Benjamin E Deverman
• 金额: $ 129.11万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-17 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669493
• 关键词: Acceleration; Adult; Area; Award; Biodistribution; Biological Assay; Biology; Biotechnology; Brain Diseases; Callithrix; Capsid; Cell Culture Techniques; Cells; Central Nervous System; Collaborations; DNA; Development; Disease; Dose; Endotoxins; Engineering; Formulation; Funding; Gene Delivery; Genes; Genome; Goals; Grant; Guidelines; Hand; Human; In Vitro; Investigational New Drug Application; Knowledge; Laboratories; Lead; Leadership; Machine Learning; Mammals; Measures; Modeling; Molecular Conformation; Mus; Mycoplasma; Neurodegenerative Disorders; Patients; Plasmids; PrP; PrP gene; Pre-Clinical Model; Prion Diseases; Prions; Process; Production; Proteins; Quality Control; Research; Resources; Role; Scientist; Technology Transfer; Testing; Tissues; Tropism; Viral; adeno-associated viral vector; arm; base editing; delivery vehicle; epigenome editing; gene delivery system; gene therapy; improved; in vivo; inflammatory marker; manufacture; multidisciplinary; nonhuman primate; novel; particle; preclinical study; prevent; therapeutic genome editing; therapy design; tissue preparation; trait; vector; vector genome

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.

摘要 — 资源核心 朊病毒病是一种由朊病毒蛋白（PrP）引起的致命且无法治愈的神经退行性疾病。朊蛋白, 由染色体基因 PRNP 编码并在所有哺乳动物中普遍表达，其不具有致病性 天然状态，但当它错误折叠成能够在构象上破坏其他物质的“朊病毒”时会引起疾病 PrP 分子。联合该提案的所有方面的目标是开发一种单剂量、永久性降低 PrP 的药物 用于治疗、预防或延缓朊病毒病的基因疗法。我们的多学科团队结合了领导力 忠诚的患者科学家、朊病毒生物学家和首席 PI Sonia Vallabh 拥有相关的尖端专业知识 David Liu 团队的碱基编辑、Jonathan Weissman 实验室的表观基因组编辑以及交付 Ben Deverman 实验室的矢量工程和制造，将作为矢量核心。 该提案的所有领域都需要能够显着增强 CNS 的载体 针对人类患者以及临床前模型的这种全脑疾病的基因传递。这种需要使得 传递载体工程的新突破以及载体专业知识的整合至关重要 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， 德弗曼实验室设计了改进的中枢神经系统递送载体，并建立了一个平台 系统地识别具有与基因治疗相关的多种特征的其他载体。该提案将 将这些正在进行的项目中的顶尖候选人应用于降低 PrP 基因疗法的开发。这 由 Deverman 博士领导的矢量工程资源核心将承担工艺开发、生产、 递送载体的配制和表征，以支持本研究中所有三个项目的体内研究 提议;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。在这个总体背景下 根据提案，资源核心将支持通过单一方法改变朊病毒疾病治疗的核心目标 剂量疗法，并为工程递送的应用提供基础概念验证 对成人患者进行系统性中枢神经系统基因治疗的载体。