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Endothelial-targeted adenovirus for organ-selective gene editing in vivo

用于体内器官选择性基因编辑的内皮靶向腺病毒

基本信息

批准号：
9810634
负责人：
David Terry Curiel
金额：
$ 71.51万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9810634
关键词：
Address Adenovirus Vector Adenovirus hexon capsid protein Adenoviruses Animal Model Animal Testing Antibodies Binding Proteins Biological Biological Models CRISPR/Cas technology Capsid Cells Collaborations Complex Disease Endothelium Engineering Gene Delivery Gene Transfer Genes Genetic Transduction Hemophilia A Hereditary Disease Human Immunity Knock-in Macaca mulatta Methods Modification Molecular Mutation Organ Pathway interactions Phase Proteins Recombinant Proteins Reporter Genes Serum Site Site-Directed Mutagenesis Somatic Cell Source System Technology Testing Therapeutic Intervention Tissues Tropism Vascular Endothelium Viral Vector adenoviral-mediated adenovirus mediated delivery alpha 1-Antitrypsin Deficiency base cellular targeting clinical translation design gene therapy genome editing in vivo novel novel strategies nuclease overexpression particle practical application scale up therapeutic gene tool vector

项目摘要

PROJECT SUMMARY A wide range of biological applications have derived from the CRISPR/Cas9 site-specific nuclease system in recent years. Of note, the capacity to accomplish gene editing in a targeted manner has also impacted the design of gene therapy strategies for an expanding repertoire of disorders. Critical to realizing the gene editing functions of the CRISPR/Cas9 system in a gene therapeutic context is the requirement to accomplish effective co-delivery in vivo of the constituent components. This delivery issue has been approached applying both non-viral and viral vector systems. In selected instances, successful gene-editing facilitated gene therapies have been accomplished in model systems of inherited genetic disease. Despite these elegant proof-of-principle studies, limits in available vector technology have greatly restricted the application of CRISPR/Cas9-facilitated gene therapy. In this regard, effective in vivo co-delivery of CRISPR/Cas9 to target somatic cells is required for many of these applications. Such delivery should be restricted exclusively to the key cellular targets in vivo to minimize off-target effects. In addition, the mandated co-delivery must be accomplished in the potential presence of pre-formed anti-vector immunity. Finally, methods to limit Cas9 expression must be endeavored to limit the potential of off-target editing. Of note, these functionalities should ideally be configured into the context of a single vector particle context to facilitate practical upscaling and human clinical translation. To this end, we have exploited the molecular promiscuities of adenovirus (Ad) to address the requirements of CRISPR/Cas9-facilitated gene therapy. In this regard, we have endeavored capsid engineering of adenovirus to achieve targeted modifications of vector tropism. In addition to allowing for re-directed tropism, capsid engineering provides the means to allow Ad to circumvent pre-formed vector immunity. We have also applied a strategy of capsid engineering to accomplish transient expression of heterologous proteins. On this basis, during the UG3 Phase (3 years) we will establish proof-of-principle with respect to delivery of genome editing machinery into disease relevant cells and tissues in vivo. The follow-on UH3 Phase (1 year) will address scale up and testing of our novel approach in a large animal model. This will be accomplished in collaboration with the SCGE Large Animal Testing Centers.

项目总结