Activating Gene Expression with Antigene RNAs to Treat Genetic Diseases

描述（由申请人提供）：常见的遗传性疾病肌营养不良症（MD）、脊髓性肌萎缩症（SMA）和脆性X综合征（FXS）对儿童发育有严重影响。它们的共同点是，它们可以通过增加单个疾病相关基因的表达来治疗。然而，由于大多数药物的非特异性作用，基因表达的药理学激活通常不被认为是治疗性治疗的选择。最近，Corey实验室发现了一种用于增加选择基因表达的强大而特异的方法。小双链RNA，称为反基因RNA（agRNA），靶向基因启动子以开启转录。这些agRNA实际上与跨越基因启动子的普遍存在的非编码RNA相互作用，以引起局部染色质结构的变化，从而导致基因表达增加。MD、SMA和FXS的疾病相关基因都具有与其基因启动子区相关的非编码RNA，并且其启动子是成功使用agRNA的明确的重要特征。拟议的研究将充分表征跨越每个疾病相关基因启动子的非编码RNA转录本。然后，agRNA将被设计成靶向疾病相关的基因启动子，并被筛选以鉴定那些可以激活基因表达的启动子。最后，agRNA介导的基因激活的关键特征将被研究，以了解agRNA的机制，并帮助建立有效的agRNA设计规则。这项研究的结果将为开发agRNA作为新型治疗药物奠定基础，以最终治疗需要增加特定基因表达的衰弱性遗传疾病，如MD，SMA和FXS。肌肉萎缩症、脊髓性肌萎缩症和脆性X综合征只是许多使人衰弱的疾病中的一小部分，这些疾病会破坏儿童的正常发育，导致生活质量低下，寿命大大缩短。这些疾病的治疗通常在于增加选择基因的表达，这不是目前可用药物的选择。这项研究的结果将为抗基因RNA作为潜在的基因特异性药物提供证据，并首次为治疗许多需要基因表达特异性增加的疾病打开大门。

DESCRIPTION (provided by applicant): The common genetic diseases muscular dystrophy (MD), spinal muscular atrophy (SMA) and fragile X syndrome (FXS) have crippling effects on childhood development. They share in common the fact that they can potentially be treated by increasing expression of a single disease-related gene. However, pharmacological activation of gene expression is not typically considered an option for therapeutic treatments due to the non-specific effects of most drugs. Recently the Corey laboratory discovered a robust and specific method for increasing expression of select genes. Small duplex RNAs, called antigene RNAs (agRNAs), are targeted to gene promoters to turn on transcription. These agRNAs actually interact with ubiquitous non-coding RNAs that span gene promoters to elicit changes in local chromatin structure, thus resulting in increased gene expression. The disease-related genes for MD, SMA and FXS all have non- coding RNAs associated with their gene promoter regions and their promoters are well-defined, important features for the successful use of agRNAs. The proposed research will fully characterize non-coding RNA transcripts that span the promoter of each disease-related gene. agRNAs will then be designed to target disease-related gene promoters and screened to identify those that can activate gene expression. Finally, key features of agRNA-mediated gene activation will be investigated to understand agRNA mechanism and help establish efficient agRNA design rules. The results of this study will lay the groundwork for developing agRNAs as novel therapeutic agents to ultimately treat debilitating genetic diseases like MD, SMA and FXS that require increased expression of specific genes. Muscular dystrophy, spinal muscular atrophy and fragile X syndrome are just a few of the many debilitating disorders that disrupt proper childhood development, resulting in a poor quality of life and dramatically shortened lifespans. Treatments for these diseases often lie in increasing the expression of select genes, which is not an option with currently available drugs. The results from this proposed research will provide evidence for antigene RNAs as potential gene-specific drugs and open the door for the first time to treatments for many diseases that require specific increases in gene expression.