Illuminating gene therapy

照亮基因疗法

基本信息

批准号：
10573764
负责人：
MICHAEL T MCMANUS
金额：
$ 20.19万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10573764
关键词：
Acceleration Adenine Animal Model Animals CRISPR/Cas technology Cell model Cells Clinic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Communities Cytosine DNA cassette Data Data Reporting Development ES Cell Line Engineering Ensure Fluorescence Genes Goals Histology Laboratories LacZ Genes Liver Luciferases Measurement Modality Mus Nature Organ Outcome Patients Positioning Attribute Postdoctoral Fellow Proteins Race Reagent Reporter Reporter Genes Reproducibility Research Research Personnel Safety Solid Neoplasm Stains System Technology Testing Therapeutic Time Tissues Transgenes Transgenic Organisms Validation Visual Work Writing base editing base editor clinical application cost design ds-DNA efficacious treatment embryonic stem cell experimental study flexibility gene therapy human disease in vivo monomer mouse development mouse genetics mouse model novel prime editing prime editor redshift research study sensor standard care

项目摘要

PROJECT SUMMARY In this project, we will develop a new mouse model for quantitating gene therapy. To promote rigor and reproducibility, we move away from single gene reporter systems and transition to multiplexed reporter configurations that are amenable for a broad range of gene editing embodiments. Specifically, we have designed an expression cassette composed of a monomeric near-infrared fluorescence protein suitable for deep tissue measurements, a LacZ transgene that provides a rapid visible stain in whole organs and histology sections, and laboratory evolved red-shifted luciferase that is designed for highly sensitive in vivo measurements. This flexible configuration will benefit the research community, offering multiple readout options for investigators. The described mouse is engineered to detect a broad range of editing embodiments including Cytosine Base Editors, Adenine Base Editors, Prime-Editors, CasFx, and perhaps others. This ‘all-in-one’ design will allow researchers to minimize the number of animals needed, thus saving time and cost. It also promotes rigor and reproducibility since different editing technologies that use the same animal can be more readily quantitatively compared between research studies performed by different groups, using different delivery agents and CRISPR embodiments. As of this writing, there are no such mouse models available, hence this project will provide a novel and unique reagent for the gene therapy field. We have assembled a strong team to tackle this project, guided by experts in base editors and prime editors (David Liu and Jennifer Doudna) and mouse genetics (Michael McManus). The project also brings on board a postdoc co-investigator with expertise in gene therapy in mouse models (Wilson Poon) who has developed a mouse sensor designed for wtCas9 gene editing. Growing momentum and an ever-increasing body of evidence indicates that base editors and prime editors will become front-runners in the race to clinical therapeutics. The development of mouse models will greatly accelerate our goal to bring gene editing to the clinic, helping to ensure a safer and more efficacious treatment.

项目概要在这个项目中，我们将开发一种用于定量基因治疗的新小鼠模型，以促进 ligor 和为了重现性，我们从单基因报告系统转向多重报告系统具体来说，我们有适合广泛基因编辑实施例的配置。设计了一个由单体近红外荧光蛋白组成的表达盒，适用于深层组织测量，一种 LacZ 转基因，可在整个器官和组织学中提供快速可见的染色切片和实验室进化的红移荧光素酶，专为体内高度敏感而设计这种灵活的配置将有利于研究界，提供多种读数。调查人员的选择。所描述的鼠标被设计用于检测广泛的编辑实施方案，包括胞嘧啶碱基编辑器、Adenine Base 编辑器、Prime-Editors、CasFx 以及其他可能的“一体化”设计将允许。研究人员最大限度地减少所需的动物数量，从而节省时间和成本。重复性，因为使用同一动物的不同编辑技术可以更容易地定量比较不同组使用不同递送剂进行的研究截至撰写本文时，尚无此类小鼠模型，因此该项目将为基因治疗领域提供一种新颖独特的试剂。我们组建了一支强大的团队来解决这个项目，并由基础编辑和主要编辑专家指导（David Liu 和 Jennifer Doudna）和小鼠遗传学（Michael McManus）该项目还引入了博士后联合研究员，具有小鼠模型基因治疗方面的专业知识（Wilson Poon），他开发了一种专为 wtCas9 基因编辑而设计的鼠标传感器不断增长的势头和不断增加的体量。有证据表明，碱基编辑器和主要编辑器将成为临床竞赛中的领跑者小鼠模型的开发将大大加速我们将基因编辑带入人类的目标。诊所，帮助确保更安全、更有效的治疗。