Activating Gene Expression with Antigene RNAs to Treat Genetic Diseases

用抗原 RNA 激活基因表达来治疗遗传性疾病

• 批准号: 8197067
• 负责人: Keith Thomas Gagnon
• 金额: $ 5.39万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197067
• 关键词: Cells; Chemistry; Childhood; Chromatin; Chromatin Structure; Code; Complementary DNA; DNA; Databases; Development; Disease; FMR1; FMR1 Gene; Fragile X Syndrome; Functional Magnetic Resonance Imaging; Functional RNA; Gene Activation; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genomics; Hereditary Disease; Higher Order Chromatin Structure; Histone Acetylation; Histones; Laboratories; Longevity; Mediating; Messenger RNA; Methods; Methylation; Molecular Target; Muscular Dystrophies; Patients; Pharmaceutical Preparations; Promoter Regions; Proteins; Quality of life; RNA; RNA Polymerase II; Recruitment Activity; Research; Reverse Transcription; SMN2 gene; Small Interfering RNA; Spinal Muscular Atrophy; Structure; Therapeutic; Therapeutic Agents; Time; Transcript; Utrophin; antigene; chromatin remodeling; design; novel therapeutics; promoter; research study

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.

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。它们的共同点是可以通过增加单个疾病相关基因的表达来治疗它们。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的选择。最近，科里实验室发现了一种强大且特定的方法来增加选定基因的表达。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实际上与普遍存在的跨基因启动子的非编码RNA相互作用，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域相关的非编码RNA，并且它们的启动子是明确定义的、对于成功使用agRNA的重要特征。拟议的研究将全面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 将被设计为针对疾病相关基因启动子，并进行筛选以识别那些可以激活基因表达的启动子。最后，将研究agRNA介导的基因激活的关键特征，以了解agRNA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作为新型治疗剂奠定基础，以最终治疗需要增加特定基因表达的MD、SMA和FXS等衰弱性遗传疾病。肌营养不良症、脊髓性肌萎缩症和脆性 X 综合征只是众多破坏儿童正常发育的衰弱性疾病中的一小部分，这些疾病会导致生活质量差和寿命急剧缩短。这些疾病的治疗方法通常在于增加特定基因的表达，而目前可用的药物无法做到这一点。这项拟议研究的结果将为反基因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特异性增加基因表达的疾病打开大门。