The RNA-activation platform to treat X-linked disease in a locus-specific manner.

RNA 激活平台以位点特异性方式治疗 X 连锁疾病。

• 批准号: 8642462
• 负责人: JEANNIE T LEE
• 金额: $ 30.58万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8642462
• 关键词: Antisense Oligonucleotides; Binding; Cells; Code; Complex; DNA Methylation; Deacetylation; Development; Disease; Disease model; Dosage Compensation (Genetics); Drug Design; Drug Industry; Duchenne muscular dystrophy; Elements; Epigenetic Process; Equilibrium; Female; Fragile X Syndrome; Gene Activation; Gene Expression; Gene Silencing; Generations; Genes; Heterochromatin; Histone H3; Histones; Human; Knowledge; Laboratories; Legal patent; Licensing; Link; Lysine; Malignant Neoplasms; Mammals; Mediating; Methodology; Methods; Methylation; MicroRNAs; Modality; Modeling; Modification; Mus; Mutation; Patients; Pharmacologic Substance; Plague; Polycomb; Positioning Attribute; Preclinical Testing; Process; Proteins; RNA; RNA Interference; Research; Rett Syndrome; Site; Small RNA; Specificity; Tail; Technology; Testing; Therapeutic; Tissues; Untranslated RNA; Work; X Chromosome; X Inactivation; gene repression; human disease; in vivo; innovation; interest; male; mouse model; next generation; pre-clinical; public health relevance; small molecule; success; tool; transcriptome sequencing

DESCRIPTION (provided by applicant): The proposed research will develop methods of upregulating X-linked genes through technical innovations applied to the original "RNA-activation" technology developed in my laboratory (RNA-a; patent pending, PCT- US2011-065939). If successful, this next-generation RNA-a methodology will have the potential to cure dozens of intractable X-linked diseases such as Rett syndrome, Fragile X syndrome, and Duchenne muscular dystrophy. In the pharmaceutical industry, current therapeutic strategies focus almost exclusively on protein and microRNA targets. Yet, lncRNAs confer a temporal and spatial specificity not possible with proteins and small RNAs, and disease-associated mutations occur more often in noncoding than coding space. Therapeutic strategies might be as effectively targeted at long noncoding RNAs (lncRNA). Indeed, designing drugs against site-specific cis-acting lncRNAs would circumvent the pleiotropic effects plaguing modalities that general activities of epigenetic complexes via small molecules. The first-generation RNA-a strategy reawakens epigenetically silenced genes by disrupting binding between Polycomb repressive complex 2 (PRC2) and the lncRNA that targets it to the locus of interest. The RNA-a technology achieves the opposite of RNAi and has proven efficacious for various disease genes in preclinical testing. However, X-linked disease genes have not been amenable to RNA-a, likely because of many additional layers of heterochromatin resulting from X- chromosome inactivation (XCI). XCI is the mechanism of dosage compensation in mammals in which one X- chromosome is silenced in female cells to balance gene expression with male cells. My laboratory has specialized in the study of XCI for the past 16 years and recently discovered X-linked elements involved in the spreading of XCI along the inactive X chromosome (Xi). From these discoveries, we hypothesize that it should be possible to selectively reawaken specific Xi loci, without reactivating most or all of the Xi. Indeed, reactivating the entire Xi would be undesirable, as we have shown that global X-reactivation results in cancer. Thus, treating X-linked diseases requires a locus-specific approach to gene activation. With newfound knowledge of how XCI spreads, the envisioned next-generation RNA-a technology has the potential to do this. Because of our expertise in XCI and RNA-a, my lab is in a unique position to further develop the RNA-a technology to unlock expression of Xi genes in a locus-specific manner. Herein we propose to achieve this by leveraging gene-specific control elements along the Xi to reactivate the model disease gene, MECP2.

描述（由申请人提供）：拟议的研究将通过应用于我的实验室中开发的原始“ RNA激活”技术的技术创新来开发上调X连锁基因的方法（RNA-A; PATENT申请，PCT-US2011-065939）。如果成功的话，这种下一代RNA-A方法将有可能治愈数十种棘手的X连锁疾病，例如RETT综合征，脆弱的X综合征和Duchenne肌肉营养不良。在制药行业中，当前的治疗策略几乎完全关注蛋白质和microRNA靶标。然而，LNCRNA赋予蛋白质和小RNA不可能的时间和空间特异性，并且与疾病相关的突变在非编码中比编码空间更频繁地发生。治疗策略可能有效地针对长的非编码RNA（LNCRNA）。实际上，针对特定位点的顺式作用lncRNA设计药物会规避多效效应的困扰方式，即表观遗传复合物通过小分子的一般活性。第一代RNA-A策略通过破坏Polycomb抑制复合物2（PRC2）和将其靶向引起的lncRNA之间的结合而逐渐估计的基因来重现遗传沉默的基因。 RNA-A技术与RNAi相反，并且在临床前测试中已被证明对各种疾病基因有效。然而，X连锁疾病基因不适合RNA-A，可能是由于X染色体灭活（XCI）引起的许多其他层异染色质。 XCI是哺乳动物中剂量补偿的机制，其中一个X-染色体在雌性细胞中沉默以平衡雄性细胞的基因表达。在过去的16年中，我的实验室专门研究XCI的研究，最近发现XCI沿着不活动的X染色体（XI）涉及的X连锁元素。从这些发现中，我们假设应该有可能选择性地重新释放特定的XI基因座，而不会重新激活大多数或全部XI。实际上，重新激活整个XI是不希望的，因为我们已经表明，全球X-反应会导致癌症。因此，治疗X连锁疾病需要特定于基因的基因激活方法。有了新发现的XCI传播知识，设想的下一代RNA-A技术有可能做到这一点。由于我们在XCI和RNA-A中的专业知识，我的实验室处于一个独特的位置，可以进一步开发RNA-A技术以特异性方式解锁XI基因的表达。本文我们建议通过利用沿XI的基因特异性控制元件来重新激活模型疾病基因MECP2，以实现这一目标。