权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Continuous Evolution of Proteins with Novel Therapeutic Potential

具有新治疗潜力的蛋白质的不断进化

基本信息

批准号：
10393666
负责人：
DAVID R LIU
金额：
$ 62.19万
依托单位：
BROAD INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10393666
关键词：
Age Agriculture Alleles Animal Model Antibodies Bacteriophages Binding Proteins Biological Process Biological Sciences Biotechnology Brain Diseases Cell model Cells Clinical Clustered Regularly Interspaced Short Palindromic Repeats DNA Development Disease Enzymes Escherichia coli Evolution Foundations Genes Genetic Diseases Genetic Models Genome Goals Guide RNA Human Human Genetics Infection Insecticides Intervention Laboratories Malignant neoplasm of brain Mediating Methods Modality Mutagenesis Mutation Neurodegenerative Disorders Peptide Hydrolases Pharmaceutical Preparations Plants Plasmids Property Proteins Proteome RNA Research Research Personnel Science Specificity System Technology Therapeutic Therapeutic Agents Time Variant base editor clinically relevant delta protein disease-causing mutation drug-sensitive functional genomics gene product genetic manipulation genome editing genomic tools human disease in vivo innovation interest macromolecule new technology next generation novel novel therapeutics nuclease prime editing prime editor protein E protein degradation research study small molecule success therapeutic development therapeutic target tool

项目摘要

Project Summary: Continuous Evolution of Proteins with Novel Therapeutic Potential The direct manipulation of genes and gene products in vivo has enormous therapeutic potential, and many strategies to achieve these goals are swiftly advancing toward clinical use. Proteins that can manipulate DNA, RNA, and proteins in living cells, including genome editing technologies that enable the precise correction of disease-causing mutations in vivo, have exemplified the promise of such approaches both for research and therapeutic applications. While many of these approaches have shown promise in initial research studies, proteins often require extensive development and tailoring to acquire the activity, specificity, and stability needed to serve as impactful research tools or leads for therapeutic development. As new macromolecular therapeutic modalities continue to be developed at a remarkable rate, methods to generate proteins on a rapid time scale with tailor-made functions are needed. Ideally such methods will be versatile and can be applied to many classes of problems in the life sciences. Our lab developed phage-assisted continuous evolution (PACE), a technology to evolve biomolecules ≥100- fold faster than using conventional laboratory evolution approaches, with minimal required researcher intervention. We have demonstrated the ability of PACE to evolve many different classes of proteins with new and altered activities, specificities, and other desirable properties such as soluble expression in E. coli. Proteins evolved using PACE have shown broad utility in multiple non-bacterial settings, including genome editing agents that have been applied to rescue human cell and animal models of genetic diseases, and insecticidal proteins that kill agricultural pests. These developments establish PACE as a broadly applicable and highly enabling technology for generating therapeutically and biotechnologically relevant proteins. We propose to apply PACE to evolve novel proteins with therapeutic potential, or that enable new technologies for therapeutics discovery. These proteins include next-generation precision genome editing agents that can be more easily delivered in vivo or are more efficient and clinically relevant; self-delivering proteases that cleave endogenous protein targets implicated in neurodegenerative disorders and brain cancer; and small molecule-binding proteins that enable drug-induced target protein degradation. Success would provide a foundation for innovative therapeutic strategies to correct mutations that cause human genetic diseases, and to reprogram self-delivering proteases as catalytic drugs to treat brain diseases. In addition, by creating drug-sensitive alleles that allow a protein of interest to be degraded in a small molecule-dependent manner, the proposed research would establish powerful new functional genomics tools to reveal biological functions and validate therapeutics targets. Collectively, the proposed research integrates powerful protein evolution technologies with enzymes that precisely manipulate genomes and proteomes to advance therapeutics science.

项目概述：具有新型治疗潜力的蛋白质的持续进化