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Novel AAVs Engineered for Efficient and Noninvasive Cross-Species Gene Editing Throughout the Central Nervous System

专为整个中枢神经系统进行高效、非侵入性跨物种基因编辑而设计的新型 AAV

基本信息

批准号：
10490394
负责人：
Benjamin E Deverman
金额：
$ 135.97万
依托单位：
BROAD INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10490394
关键词：
Address Adult Affect Animal Testing Animals Astrocytes Biological Products Blood - brain barrier anatomy Brain Callithrix Capsid Cells Central Nervous System Diseases Characteristics Clinical Clinical Trials Clinical Trials Design Collaborations Communities Dependovirus Directed Molecular Evolution Disease Engineering Ensure Enterobacteria phage P1 Cre recombinase Europe Evaluation Future Gene Delivery Gene Expression Gene Transduction Agent Gene Transfer Genes Genetic Genetic Diseases Genetic Models Human Injections Intravenous Knock-in Lead Libraries Macaca mulatta Mental disorders Methods Methyl-CpG-Binding Protein 2 Mucopolysaccharidosis II Mus Nature Neuraxis Neuroglia Neurons Pharmaceutical Preparations Phase Population Production Rattus Recovery Reporter Rhesus Rodent Safety Somatic Cell System Technology Testing Therapeutic Time Toxic effect United States National Institutes of Health Variant Virus base body system cell type early phase clinical trial gene delivery system gene therapy genome editing genome-wide improved in vivo insertion/deletion mutation interest intravenous administration lead candidate nervous system disorder next generation nonhuman primate novel pre-clinical programs scale up small molecule somatic cell gene editing success tool transduction efficiency transgene expression vector vector genome

项目摘要

Project Summary: Many genetic diseases that affect the central nervous system (CNS) remain untreatable due to a lack effective small molecule drugs or biologics. Targeting the genetic underpinnings of these diseases with somatic cell gene editing would therefore be particularly impactful, but its successful implementation will require methods to safely and efficiently deliver genes and gene editing machinery throughout the CNS. AAVs are the state-of-the-art vehicles for in vivo gene transfer because they can provide safe and long lasting in vivo gene expression. AAVs are the only gene therapy vectors that have been approved for direct administration to humans by regulatory agencies in both the US and Europe. Moreover, in 2017, AAVs became the first vehicle used as part of an early phase clinical trial to evaluate the safety of in vivo gene editing. Despite their impressive preclinical and clinical safety record, naturally occurring AAVs tested to date lack the efficiency required for gene delivery across most organ systems, including the CNS. To address the need for better vehicles for CNS gene delivery, we recently used directed evolution and a new cell type-specific in vivo selection method to engineer several novel AAVs, most notably AAV-PHP.B and AAV-PHP.eB, that have, for the first time, made it possible to noninvasively transfer genes to the majority of neurons and astrocytes throughout the adult mouse CNS. Here, we aim to build upon the success of this selection approach by engineering AAVs that enable efficient gene transfer throughout the CNS of multiple species, including nonhuman primates. The AAVs we develop will be evaluated in several species for their ability to provide CNS-wide transgene expression and targeted genome editing in neurons, and improved AAV variants will be shared with the scientific community. Successful completion of this project, which involves pairing the new AAVs with next-generation gene editing technologies, will provide support for evaluating the safety of CNS gene editing in human trials.

项目总结: