Platform for Massively Parallel Selection of Aptamer Ligands

适体配体大规模并行选择平台

基本信息

批准号：
8246723
负责人：
George W Jackson
金额：
$ 53.72万
依托单位：
BIOTEX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-15 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8246723
关键词：
Affinity Anisotropy Antibodies Automation Binding Bioinformatics Biological Assay Calorimetry Cells Coupled Custom DNA DNA Library Data Base Management Development Diagnostic Diversity Library Evaluation Fluorescence-Activated Cell Sorting Genetic Transcription Goals Hybrids Image Immunoglobulin Constant Region In Situ Individual Kinetics Label Libraries Ligand Binding Ligands Light Marketing Measures Medicine Methods Metric Nucleic Acids Oranges Output Paper Performance Pharmaceutical Preparations Phase Positioning Attribute Process Protein Array Protein Microchips Proteins Protocols documentation RNA RNA library Randomized Reaction Reporting Research Risk Robotics Safety Sequence Alignment Small Business Innovation Research Grant Specificity Spottings Structure Surface Plasmon Resonance Technology Testing Therapeutic Thermodynamics Time Translations Validation Western Blotting Work aptamer base combinatorial density drug candidate drug development interest next generation novel phase 1 study therapeutic protein tool

项目摘要

DESCRIPTION (provided by applicant): Aptamers have emerged as one of the most promising classes of drug leads and diagnostic ligands presently available. Aptamers, nucleic acid ligands derived from large combinatorial libraries, typically have affinities and specificities that rival antibodies, yet they have a number of significant advantages for therapeutic and diagnostic applications. Unfortunately, the existing process for aptamer development is low-throughput and tedious as DNA or RNA libraries are screened against only a single target. This project focuses on developing the methods and tools to allow large combinatorial to be screened against arrays of thousands of proteins simultaneously. Such protein arrays are increasing available with content of high therapeutic and diagnostic value. The key to achieving this is developing the necessary steps to decipher which aptamers (once selected) correspond to which target. So-called "next generation" sequencing will greatly enable the proposed process coupled with the necessary "sequence-tagging" approaches developed in this project. Once our massively parallel aptamer selection process is developed, we will be in a position to create high affinity aptamer ligands to thousands of proteins in roughly 1 week. The developed ligands can then be further characterized as promising drug candidates, diagnostic labels, and other research applications perhaps eventually including personalized medicine. PUBLIC HEALTH RELEVANCE: A recent white paper by the US Federal Drug Administration finds that there exists a critical problem in bringing novel drugs to market, something the FDA describes as the 'pipeline problem'. According to this and other reports drug companies spend an average of $0.8-1.7 billion dollars on the discovery, development and approval of any one individual drug. To make matters worse, the time from the initial testing of a drug candidate and to its eventual marketing can take up to 20 years. Thus, the FDA report strongly urges the incorporation of novel quantitative predictive tools for the assessment of safety and efficacy of new drug leads and diagnostic ligands early in the drug development process. This project provides for the parallel development and evaluation of enormous combinatorial libraries of DNA or RNA 'aptamers' against of thousands of protein targets of potential 'druggable' interest. If successful, the technology could provide for unprecedented throughput of drug leads and diagnostic ligands.

描述（由申请人提供）：适体已成为目前可用的最有前途的药物先导物和诊断配体类别之一。适体是源自大型组合文库的核酸配体，通常具有与抗体相媲美的亲和力和特异性，但它们在治疗和诊断应用中具有许多显着的优势。不幸的是，现有的适体开发过程通量低且繁琐，因为 DNA 或 RNA 文库仅针对单个靶点进行筛选。该项目的重点是开发方法和工具，以允许同时针对数千种蛋白质的阵列进行大型组合筛选。此类蛋白质阵列的可用性越来越高，具有高治疗和诊断价值。实现这一目标的关键是制定必要的步骤来破译哪些适体（一旦选择）对应于哪个目标。所谓的“下一代”测序将极大地实现所提出的过程以及该项目中开发的必要的“序列标记”方法。一旦开发出大规模并行适体选择流程，我们将能够在大约 1 周内为数千种蛋白质创建高亲和力适体配体。然后，开发的配体可以进一步被定性为有前途的候选药物、诊断标签和其他研究应用，可能最终包括个性化医疗。公共健康相关性：美国联邦药物管理局最近发布的一份白皮书发现，将新药推向市场存在一个关键问题，FDA 将其称为“管道问题”。根据这份报告和其他报告，制药公司平均花费 0.8-17 亿美元用于发现、开发和批准任何一种药物。更糟糕的是，从候选药物的最初测试到最终上市可能需要长达 20 年的时间。因此，FDA 报告强烈敦促在药物开发过程的早期纳入新型定量预测工具来评估新药先导物和诊断配体的安全性和有效性。该项目提供了针对数千个潜在“可成药”兴趣的蛋白质靶标的巨大 DNA 或 RNA“适体”组合文库的并行开发和评估。如果成功，该技术可以提供前所未有的药物先导物和诊断配体的吞吐量。