CRISPR/Cas-mediated development of an RNAi rat model system

CRISPR/Cas介导的RNAi大鼠模型系统的开发

基本信息

批准号：
9908231
负责人：
Prem Khovabutr Premsrirut
金额：
$ 102.04万
依托单位：
MIRIMUS, 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：
2018-08-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908231
关键词：
Adopted Advanced Development Animal Model Back Biological Models Blood specimen CRISPR/Cas technology Carcinogenicity Tests Cessation of life Characteristics Client Clustered Regularly Interspaced Short Palindromic Repeats Cognitive Contracts Custom Development Disease Drug Costs Drug usage Embryo Embryology FDA approved Failure Female Foundations Funding Future Gene Deletion Gene Expression Gene Expression Regulation Gene Silencing Gene Targeting Generations Genes Genetic Engineering Genetically Engineered Mouse Genome Genome engineering Genomics Goals Gold Hand Homing Human Immunology In Situ Investments Laboratories Lead Libraries Mammalian Oviducts Marketing Mediating Methods Modeling Modification Mus Neurobiology Operative Surgical Procedures Pathology Pharmaceutical Preparations Pharmacologic Substance Phase Phase I Clinical Trials Physiological Preclinical Testing Procedures Process Production Protocols documentation RNA Interference Rattus Reagent Reporter Research Research Personnel Resort Rivers Rodent Rodent Model Safety Scientist Services Site Small Business Innovation Research Grant Surveys System Technology Technology Transfer Therapeutic Therapeutic Intervention Therapeutic Studies Time Toxic effect Toxicity Tests Toxicology Translating Validation Work base cost cost effective cost efficient drug development drug discovery experience gene discovery genome editing human disease in vivo knockout animal knockout gene mouse model new therapeutic target novel nucleic acid delivery operation pre-clinical prevent programs promoter rat genome resistance mechanism response small hairpin RNA tool

项目摘要

Abstract The cost of drug development has skyrocketed to an estimated $2.6B for every FDA approved drug primarily due to failures from lack of efficacy or safety, suggesting that our current preclinical validation process has been insufficient in predicting therapeutic potential and toxicity in humans. Animal models are the gold standard for dissecting disease mechanisms and evaluating novel drug targets in vivo; however, the cost and long lead time to develop them has prevented their routine use in the drug discovery process. With the recent developments in CRISPR/Cas9 genome editing, and advances in RNA interference technologies, we now have the ability to rapidly develop animal models with precise genomic modifications and human-like disease pathologies. We have shown that RNAi serves as a fast alternative to gene deletion and can also be used within genetically engineered mouse models to assess the therapeutic potential and predict toxicities of novel gene targets. The goal of this proposal is to expand our capabilities beyond mice and develop a platform for rapid and cost-effective production of RNAi rats in as little as 4 months. Despite the utility of mouse models, for many scientists, the rat still remains the preferred rodent due to their larger size for surgical manipulation, repeat blood sampling, and their cognitive and physiological characteristics that more closely resemble humans than their mouse counterparts. For neurobiology, cardiobiology, immunology and toxicology, they are still the dominant rodent model in research. Nearly 30% of our current client base has inquired about rat models over the last 5 years, noting that most toxicology studies of their compounds are still done in rats prior to Phase I clinical trials. We know rats will gain popularity once again as the premier rodent model in drug discovery, as we have already been contracted a large pharmaceutical company for an initial pilot program for these models. We intend to be at the forefront of this shifting paradigm back to the rat model. Using novel in situ delivery methods of CRISPR/Cas9 reagents, we will now be able to manipulate the rat genome in a rapid and cost-efficient manner and systematically generate RNAi rat models that allow for temporal and reversible gene regulation to simulate therapeutic regimes. These RNAi rat models will transform the preclinical validation process with assessment of potential drug response and resistance mechanisms in vivo, ultimately guiding the development of safer and more effective drugs.

抽象的药物开发的成本已飙升至估计每种FDA批准的药物的估计$ 2.6B 由于缺乏功效或安全性失败，这表明我们当前的临床前验证过程已有不足以预测人类的治疗潜力和毒性。动物模型是黄金剖析疾病机制并评估体内新型药物靶标的标准；但是，成本和开发它们的长时间提前时间阻止了他们在药物发现过程中的常规使用。与最近的 CRISPR/CAS9基因组编辑的发展以及RNA干扰技术的进步，我们现在有能力快速开发具有精确基因组修饰和类似人类疾病的动物模型病理。我们已经证明RNAi是基因缺失的快速替代品，也可以使用在基因工程的小鼠模型中，以评估治疗潜力和预测新颖的毒性基因靶标。该提案的目的是扩大我们的能力以外的小鼠，并为短短4个月内，RNAi大鼠的快速和成本效益的产生。尽管鼠标具有实用性，但许多科学家，由于大鼠的手术操纵尺寸较大，因此仍然是首选的啮齿动物重复血液采样及其认知和生理特征，它们非常相似人类比老鼠对应物。对于神经生物学，心脏生物学，免疫学和毒理学，它们是仍然是研究中的主要啮齿动物模型。当前客户群的近30％都询问了老鼠在过去的5年中进行I期临床试验。我们知道，老鼠将再次成为药物的主要啮齿动物模型发现，因为我们已经签约了一家大型制药公司，用于初始试点计划这些模型。我们打算在此不断变化的范式的最前沿回到大鼠模型。使用小说 CRISPR/CAS9试剂的原位输送方法，我们现在将能够快速操纵大鼠基因组以及具有成本效益的方式，并系统地生成RNAi大鼠模型，以便于时间和可逆基因调节以模拟治疗方案。这些RNAi大鼠模型将改变临床前验证通过评估体内的潜在药物反应和耐药机制的过程，最终指导开发更安全，更有效的药物。