Chemically controlling chromatin to treat Friedriech's Ataxia

化学控制染色质治疗弗里德里希共济失调

• 批准号: 10009926
• 负责人: Nathaniel A. Hathaway
• 金额: $ 25.12万
• 依托单位: EPIGENOS BIOSCIENCE, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10009926
• 关键词: Aberrant DNA Methylation; Acetylation; Affect; Alleles; Arrhythmia; Ataxia; Automobile Driving; Binding; Bioenergetics; Biological Assay; CRISPR/Cas technology; Cardiac; Cardiomyopathies; Cell model; Cells; Chemicals; Chimeric Proteins; Chromatin; Clinical; Confocal Microscopy; Coupled; DNA Sequence; Development; Diabetes Mellitus; Disease; Engineering; Enzymes; Epigenetic Process; Expression Profiling; FDA approved; FK506; Fibroblasts; Friedreich Ataxia; Functional disorder; Galactose; Gene Activation; Gene Expression; Gene Proteins; Gene Targeting; Generations; Genes; Genetic; Genetic Transcription; Genome; Genomics; Genus Hippocampus; Guide RNA; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone H3; Histones; Hour; Individual; Introns; Iron; Lead; Link; Measures; Mediating; Metabolic; Metabolism; Methylation; Mitochondria; Mitochondrial Proteins; Modeling; Modernization; Myasthenia; Neurodegenerative Disorders; Neurologic; Nuclear; Oxygen Consumption; Pathology; Pathway interactions; Patients; Peroxidases; Pharmaceutical Preparations; Plant Roots; Polyethylene Glycols; Polymerase; Proteins; RNA delivery; Rare Diseases; Respiration; Signal Pathway; Site; Stress; System; Tacrolimus Binding Proteins; Technology; Therapeutic; Transcription Initiation Site; Virginia; Work; base; chromatin modification; clinical translation; clinically relevant; curative treatments; disease phenotype; epigenetic regulation; epigenome; experimental study; extracellular; frataxin; gene repression; human disease; inhibitor/antagonist; innovation; mRNA Expression; mitochondrial dysfunction; novel; protein expression; rare variant; scoliosis; therapeutic gene; vector

We recently developed a technology that combines catalytically inactive dCas9 with bifunctional chemicals that link endogenous host cellular machinery to specific genes targeted with dCas9. We have demonstrated this technology can significantly increase gene expression at multiple endogenous mammalian genes in a chemically dependent manner. Here we propose to apply this technology to the mono-allelic rare disease with no current cure, Friedreich’s Ataxia. This disease is caused by a GAA expansion in the first intron of the frataxin gene which leads to polymerase pausing and lower gene expression. This proposed project will evaluate if targeting the frataxin gene with our combination of protein and chemical activator can restore expression levels of frataxin to a point which reverses pathology of this disease in a modern model of Friedreich’s Ataxia. We will use patient derived Friedreich’s Ataxia models in specific assays that intricately measure mitochondria function and metabolic activity that is typically dysregulated in patients that is the hallmark of this human disease. This work has the potential to lead to new treatment paradigms for individuals afflicted by this aggressive disease.

我们最近开发了一种将催化无效DCAS9与双功能结合的技术 将内源性宿主细胞机械与DCAS9靶向的特定基因联系起来的化学物质。 我们已经证明了这项技术可以显着增加多个的基因表达 内源性哺乳动物基因以化学依赖的方式。在这里我们建议申请 弗里德里希（Friedreich）的共济失调，这项技术是单相关稀有疾病，没有目前的治疗方法。 疾病是由Frataxin基因的第一个内含子的GAA扩展引起的，该基因导致 聚合酶暂停和较低的基因表达。该提议的项目将评估是否针对 与我们的蛋白质和化学激活剂组合的Frataxin基因可以恢复表达 在现代模型的现代模型中，frataxin的水平逆转了这种疾病的病理 弗里德里希的共济失调。我们将在特定的测定中使用患者衍生的弗里德里希的共济失调模型 错综复杂的线粒体功能和代谢活性通常在 这是这种人类疾病的标志。这项工作有可能导致新 患有这种侵略性疾病的人的治疗范例。