High-throughput functional analysis and clinical relevance of all possible variants of a gene

基因所有可能变异的高通量功能分析和临床相关性

基本信息

批准号：
10601908
负责人：
Martin Schiller
金额：
$ 39.85万
依托单位：
HELIGENICS INC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-02 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10601908
关键词：
Acute Address Affect American Amino Acid Substitution Biochemical Bioinformatics Biological Biological Assay Biology Biotechnology Cause of Death Cell Cycle Progression Cell Line Cells Cessation of life Climacteric Clinical Clinical Trials Code Data Detection Development Disease Doxycycline Drug Prescriptions Drug Targeting Drug resistance Drug usage ERBB2 gene Enhancers Ethics Expression Library FDA approved Future Genes Genetic Genetic Variation Genome Genomics Goals Growth HIV Health Human Human Genetics Human Genome Legal Lentivirus Vector Libraries Life MAP Kinase Gene MCF7 cell Malignant Epithelial Cell Measures Medical Medical Genetics Methods Modernization Morbidity - disease rate NF-kappa B National Human Genome Research Institute Newborn Infant Patients Persons Pharmaceutical Preparations Pharmacologic Substance Phase Positioning Attribute Production Prognosis Protein Tyrosine Kinase Proteins Quality of life RNA Splicing Recommendation Reporter Reporting Reproducibility Resistance Services Signal Transduction Small Business Innovation Research Grant Speed Stimulation of Cancer Cell Growth Structure Surveys Technology Testing Therapeutic Transfection Tyrosine Kinase Domain Tyrosine Kinase Inhibitor United States United States National Institutes of Health Variant Viral Work cDNA Library chemotherapy clinical effect clinical trial analysis clinically relevant clinically significant cost design disease diagnosis dosage drug action drug development drug efficacy feasibility testing genetic element genetic testing genetic variant improved innovation interest medical schools mortality mutant novel novel strategies novel therapeutics promoter public database resistance mutation response screening trait transcription factor variant of unknown significance

项目摘要

Modern pharmaceuticals have greatly improved the quality of life for many patients suffering a variety of illnesses. Unfortunately, among the 17 most commonly prescribed drugs, only 6 are highly effective for most patients, 5 have a modest effect, and 6 show little clinical effect. Worse still, unwanted illness and death from treatment of patients with the incorrect drug or dosage causes over 275,000 unnecessary deaths annually in the United States, making it the 3rd-leading cause of death. Genomic screening can minimize the loss of lives by clearly defining the cause-and-effect between a patient’s genetic sequence and their disease. Many gene sequences are known to affect a person’s response to drugs. The FDA lists over 450 warnings or recommendations for drug use based on possible genetic variants in specific genes. Other public databases list ~60,000 “characterized” gene variants, but their importance is often unknown. Moreover, these variants represent a vanishingly small fraction of >900 million known human genetic variations. The vast number of “Variants of Uncertain Significance” (VUS) present potentially life-altering medical, ethical, legal, and societal complications. Some cause drugs to be more or less effective in different patients. Others can stimulate growth of cancer cells or make those cells resistant to chemotherapies. To understand the biological impact of gene variants, Heligenics has developed the GigaAssay™ technology to measure the functional effect of all variations within any selected gene. In contrast to similar technologies, the GigaAssay reports the activity of each variant of the gene, with high accuracy and reproducibility. In this proposal, we plan to improve the GigaAssay and show its feasibility for detection and analysis of gene variants that have clinical importance. In Aim 1 we will create a battery of GigaAssay cell lines and readouts for rapid analysis of several functional cellular activities. In Aim 2 we will demonstrate that the GigaAssay can detect gene variants that cause resistance to an FDA-approved chemotherapy drug. This work will directly address numerous goals of the “Illuminating the Druggable Genome” project of the NIH. Future plans include expanding the number of GigaAssays, increasing the speed or number of genes that can be studied, and partnering with drug developers and clinical trial managers to identify the optimal drug for each patient, based on his or her genetic variants.

现代药品大大改善了许多患有多种疾病的患者的生活质量。不幸的是，在17种最常见的药物中，只有6种对大多数患者来说是非常有效的，5个具有适度的效果，6几乎没有临床作用。更糟糕的是，不必要的疾病和治疗死亡统一的药物或剂量不正确的患者每年导致超过275,000例不必要的死亡国家，使其成为第三大领先的死亡原因。基因组筛查可以通过明确定义患者的因果关系来最大程度地减少生命的丧失遗传序列及其疾病。已知许多基因序列会影响一个人对药物的反应。 FDA根据特定的遗传变异列出了450多个警告或有关药物使用的建议基因。其他公共数据库列出了约60,000个“特征”基因变体，但其重要性通常是未知的。此外，这些变体代表了> 9亿人类已知的人类遗传变异的一小部分。大量“具有不确定意义的变体”（VUS）提出了潜在的改变生活的医学，道德，法律和社会并发症。有些导致药物在不同患者中或多或少有效。其他人可以刺激癌细胞的生长或使这些细胞抗化疗。为了了解基因变体的生物学影响，Heligenics已开发了Gigaassay™技术测量任何选定基因中所有变化的功能效应。与类似技术相比 Gigaassay以高精度和繁殖报告了基因的每个变体的活性。在此提案中，我们计划改善gigaassay并显示其对基因的检测和分析的可行性具有临床重要性的变体。在AIM 1中，我们将创建一系列Gigaassay单元线和读数快速分析几种功能性细胞活性。在AIM 2中，我们将证明Gigaassay可以检测到引起FDA批准化疗药物抗性的基因变异。这项工作将直接解决NIH的“照明可毒品基因组”项目的众多目标。未来的计划包括扩大Gigaassay的数量，增加可以进行研究，并与药物开发人员和临床试验经理合作，以识别每个病人，基于他或她的遗传变异。