Research Core (Deverman)

研究核心（德弗曼）

基本信息

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
项目类别：
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

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

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项目摘要

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 Prion疾病是由Prion蛋白（PRP）引起的致命，不可治疗的神经退行性疾病。 PRP，由染色体基因PRNP编码并在所有哺乳动物中均匀表达，在其中并非致病性本地国家，但当疾病变成能够构象腐败其他人的“ prion”时会引起疾病 PRP分子。联合本提案的所有武器的目标是开发一种单剂量，永久性降低PRP 基因治疗，以治疗，预防或延迟病毒疾病。我们的多学科团队结合了致力于患者科学家，王室生物学家和铅pi sonia vallabh具有尖端专业知识戴维·刘集团（David Liu Group）的基础编辑，乔纳森·韦斯曼（Jonathan Weissman）实验室的表观基因组编辑和交付 Ben Deverman实验室的向量工程和制造，该实验室将作为向量核心。交叉切割本提案的所有领域都是对矢量的需求，这些向量可以大大增强CNS 人类患者以及临床前模型的整个脑疾病的基因递送。这需要至关重要的是在交付矢量工程中的新突破以及矢量专业知识的整合生物学，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 Lab已为CNS设计了改进的交付向量，并建立了一个平台系统地识别具有与基因疗法相关的多种特征的其他向量。该提议将将这些正在进行的项目的顶级候选人应用于开发降低PRP基因疗法的发展。由Deverman博士领导的向量工程资源核心将进行过程开发，生产，形成和表征交付向量以支持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，并为尺度制造提供技术转移和监督。在整个情况下提案，资源核心将基于通过单一转化病毒疾病疗法的核心目标剂量疗法，还提供了用于应用工程交付的基础概念证明成人人类患者的系统管理中枢神经系统疗法的向量。