Chemically controlling chromatin to treat Friedriech's Ataxia

我们最近开发了一种技术，该技术将催化失活的dCas9与双功能 将内源性宿主细胞机制与dCas9靶向的特定基因联系起来的化学物质。 我们已经证明，这项技术可以显着增加基因表达在多个 内源性哺乳动物基因以化学依赖的方式。在此，我们建议申请 这项技术用于目前无法治愈的单等位基因罕见疾病，弗里德赖希共济失调。这 这种疾病是由共济失调蛋白基因第一内含子中的GAA扩增引起的， 聚合酶暂停和降低基因表达。本拟议项目将评估是否针对 Frataxin基因与我们的蛋白质和化学激活剂的组合可以恢复表达 水平的frataxin到逆转这种疾病的病理学的一个点，在一个现代模型， 弗里德赖希共济失调。我们将在特定测定中使用患者来源的Friedreich共济失调模型， 复杂地测量线粒体功能和代谢活性， 这是人类疾病的标志。这项工作有可能导致新的 治疗模式的个人折磨这种侵略性疾病。

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.