Urgent Supplement: Correcting genetic disorders using predictable CRISPR/Cas9-induced exon skipping

紧急补充：利用可预测的 CRISPR/Cas9 诱导的外显子跳跃来纠正遗传疾病

基本信息

批准号：
10163567
负责人：
Christopher Cassa
金额：
$ 13.98万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10163567
关键词：
2019-nCoV Affect Animals Antiviral Agents COVID-19 CRISPR screen CRISPR/Cas technology Candidate Disease Gene Cell Line Clinical Clinical Data Clinical Trials Data Disease Disease Outbreaks Disease Progression Dose Drug Interactions Drug toxicity Drug usage Early treatment Ensure Enzymes Genes Genetic Genetic Diseases Genetic Screening Genetic study Genomic approach Genomics Human Human Genetics Immune response Immunity In Vitro Individual Intestines Literature Liver Mediating Methods Modeling Morbidity - disease rate Nature Nutrient Organoids Outcome Pathogenicity Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Process RNA-Directed RNA Polymerase Risk Safety Testing Therapeutic Intervention Time TimeLine Toxic effect Variant Viral Viral Proteins Virus clinical efficacy cytotoxicity disorder control drug candidate effective therapy exon skipping experimental study genetic association genetic testing genetic variant genome wide association study genome-wide improved insight loss of function mortality novel strategies novel therapeutics patient population patient screening remdesivir research clinical testing screening targeted treatment therapeutic candidate therapeutic evaluation transcriptome sequencing

项目摘要

Project Summary The rapid spread of SARS-CoV2 presents an unprecedented challenge to urgently control disease morbidity, mortality, and spread. Antiviral drugs including remdesivir, favipiravir, and EIDD-2801 have emerged as front-line treatments. However, there are toxicity concerns for these drugs, especially as they are most effective when given at high doses early in disease progression. The ability to administer these antivirals more safely, particularly in less severely affected individuals, will allow for earlier treatment. In this project, we combine experimental genomic approaches and genetic association studies to understand and mitigate toxicity of SARS-CoV-2 antiviral drugs. In Aim 1, we will use state-of-the-art genomic screening to identify human genes that mediate toxicity of SARS-CoV-2 antiviral drugs in liver and intestinal cell lines. In Aim 2, we will examine genetic associations of remdesivir efficacy and toxicity from ongoing clinical trials. In Aim 3, we will combine this information to test approved pharmaceuticals or nutrients which are known to target or interact with genes we identify to determine if any mitigate drug cytotoxicity. We will also determine whether there are any common genetic or disease conditions for which antiviral dosing may be inadvisable. Altogether, we aim to provide rapid and actionable insight on the toxicity of front-line SARS-CoV-2 antiviral drugs.

项目概要 SARS-CoV2的快速传播对紧急控制疾病提出了前所未有的挑战发病率、死亡率和传播。瑞德西韦、法匹拉韦和 EIDD-2801 等抗病毒药物已成为一线治疗方法。然而，这些药物存在毒性问题，特别是当在疾病进展早期给予高剂量时最有效。管理能力这些抗病毒药物更安全，特别是对于受影响较轻的个体，将可以更早地治疗。在这个项目中，我们结合了实验基因组方法和遗传关联了解和减轻 SARS-CoV-2 抗病毒药物毒性的研究。在目标 1 中，我们将使用最先进的基因组筛选来识别介导毒性的人类基因 SARS-CoV-2 抗病毒药物在肝和肠细胞系中的作用。在目标 2 中，我们将检查遗传正在进行的临床试验中瑞德西韦疗效和毒性的关联。在目标 3 中，我们将结合此信息用于测试已知可靶向或相互作用的已批准药物或营养素我们确定基因以确定是否有任何减轻药物细胞毒性的基因。我们还将确定是否有是不建议使用抗病毒药物的任何常见遗传或疾病状况。总而言之，我们的目标是对一线 SARS-CoV-2 的毒性提供快速且可行的见解抗病毒药物。