Synthetic molecules to stimulate the expression of Frataxin to ameliorate Freidreichs Ataxin

项目总结/摘要 弗里德赖希共济失调（FRDA/FA）是最常见的常染色体隐性遗传性神经退行性疾病 无法治愈这种使人衰弱并最终致命的疾病的发生是由于以下因素的表达减少： 共济失调蛋白（FXN），一种在线粒体中的铁代谢中起作用的核编码蛋白。纯合 FXN沉默mRNA合成的第一内含子中GAA三联体重复的扩增。FXN蛋白 缺乏导致进行性神经变性、肥厚性心肌病甚至糖尿病。一 靶向FXN中GAA重复扩增的新型合成转录延伸因子（Syn-TEF） 并积极刺激沉默基因的Pol II功能。在病人- 通过使用衍生细胞，Syn-TEF 1将FXN恢复到在健康个体中观察到的水平。这背后的前提是 建议系统评价Syn-TEF对表观遗传景观和/或 稳定的不寻常DNA结构的形成将揭示这些机制在多大程度上起作用 到患者来源的细胞中的FXN沉默。这种理解将导致更多的机械引导设计， 下一代精确定制的Syn-TEFs此外，在FXN缺乏的细胞类型中测试Syn-TEFs， 导致共济失调和发病率是发展基因组靶向精确治疗的第一步。

PROJECT SUMMARY/ABSTRACT Friedreich's ataxia (FRDA/FA) is the most commonly inherited autosomal recessive neurodegenerative disease for which there is no cure. This debilitating and ultimately lethal disease occurs due to reduced expression of frataxin (FXN), a nuclear encoded protein that plays a role in iron metabolism in mitochondria. Homozygous expansion of GAA triplet repeats in the first intron of FXN silence mRNA synthesis. The resulting FXN protein deficiency leads to progressive neurodegeneration, hypertrophic cardiomyopathy and even diabetes mellitus. A novel class of synthetic transcription elongation factors (Syn-TEFs) that target GAA repeat expansions in FXN and actively stimulate Pol II function across the silenced gene were recently developed by our group. In patient- derived cells, Syn-TEF1 restores FXN to levels observed in healthy individuals. The premise that underlies this proposal is that systematic evaluation of the Syn-TEF responsive changes in the epigenetic landscape and/or the formation of stable unusual DNA structures will reveal the extent to which of these mechanisms contribute to FXN silencing in patient-derived cells. This understanding will result in more mechanistically-guided design of the next generation precision-tailored Syn-TEFs. Moreover, testing Syn-TEFs in cell types where FXN deficiency results in ataxia and morbidity is a first step toward the development of genome-targeted precision therapeutics.