Comprehensive Deep Phenotyping and Multi-omics to Develop Clinical and Molecular Biomarkers for MeCP2-related Diseases

全面的深度表型分析和多组学开发 MeCP2 相关疾病的临床和分子生物标志物

• 批准号: 10526111
• 负责人: Davut Pehlivan
• 金额: $ 21.03万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10526111
• 关键词: Affect; Alleles; Antisense Oligonucleotides; Automobile Driving; Biliverdine; Binding Proteins; Biological Markers; Blood specimen; Boston; Brain; Brain region; Cell Nucleus; Child; Chromatin; Clinical; Clinical Trials; Complex; Country; DNA Sequence Rearrangement; Development; Disease; Dose; Drops; Enrollment; Female; Genes; Genetic; Genomics; Genotype; Heme; Human; Intellectual functioning disability; Link; MeCP2 Duplication Syndrome; Measurable; Measurement; Measures; Mentors; Methyl-CpG-Binding Protein 2; Modality; Moods; Mus; Natural History; Neurodevelopmental Disorder; Neurons; Nuclear; Office Visits; Optics; Outcome Measure; Patients; Pediatric Hospitals; Phenotype; Phosphoric Monoester Hydrolases; Phosphotransferases; Physical Examination; Population; Positioning Attribute; Proteins; Recording of previous events; Resolution; Rett Syndrome; Severities; Severity of illness; Structure; Symptoms; Texas; Therapeutic; Universities; Visit; Western Blotting; Wild Type Mouse; Work; biomarker panel; candidate marker; clinical biomarkers; clinical diagnostics; clinical outcome measures; cohort; comparative genomic hybridization; diagnostic criteria; disabling symptom; gene product; genome sequencing; human subject; humanized mouse; loss of function mutation; lymphoblast; male; molecular marker; motor control; multiple omics; patient population; preclinical study; prevent; treatment response; whole genome

Abstract The X-linked gene MECP2 (methyl CpG-binding protein 2) is associated with two major neurodevelopmental disorders: Rett Syndrome (RTT), caused by loss-of-function mutations in MeCP2, and MECP2 duplication syndrome (MDS), caused by too much MeCP2. RTT is one of the most common genetic causes of intellectual disability in females, while (MDS) is one of the most common genomic rearrangements in males. Because the MeCP2 protein regulates the expression of thousands of genes across multiple brain regions, the phenotype of each disease extends well beyond intellectual disability to affect mood, motor control, and autonomic functions1. The brain is exquisitely sensitive to the quantity of MeCP2: a drop of just 16% in MeCP2 levels is enough to produce Rett-like symptoms. This single fact is a salient challenge to the most promising therapies being developed for these diseases: slightly over-shooting treatment for RTT by increasing MeCP2 levels too much will cause MDS; suppressing MeCP2 levels too much in MDS will cause RTT. To avoid simply exchanging one set of debilitating symptoms for another, we need reliable ways to measure treatment responses and to assess whether we are administering the correct dose. Preclinical studies in humanized mice have convincingly demonstrated that antisense oligonucleotides (ASO) can reduce MeCP2 levels and reverse the MDS phenotype; more recent work identified kinases and phosphatases that regulate MeCP2 stability, again with good results in mice. These options are both extremely promising, but how do we measure MeCP2 levels in patients? MeCP2 is a nuclear, chromatin-bound protein that is expressed at very high levels in the brain, where it is not accessible to direct measurement. We have therefore been searching for other molecules that correlate with MeCP2 levels but are measurable in blood samples or other relatively noninvasive means. I propose that, for such complex diseases as RTT and MDS, a composite biomarker panel will be superior to any single-modality measure to judge treatment response. Our preliminary studies have already identified two important molecular biomarkers that track with MeCP2 levels in mice; we have several additional candidates as well. This study therefore aims to develop a panel of clinical and molecular biomarkers that will guide therapeutic efforts to prevent over- or under-treatment in these diseases. Texas Children's Hospital has the largest patient populations in the country for both RTT and MDS, so we are well-positioned to accomplish 1) Develop outcome measures for MDS; 2) Correlate phenotypes with the genomic structure at Xq28 locus; and 3) Validate in humans molecular biomarkers that track with changes in MeCP2 levels in mice. Completing these three aims will lay the groundwork for clinical trials of ASOs in MDS and pave the path forward for studies involving other allelic disorders involving too much or too little of the same gene product.

抽象的 X连锁基因MECP2（甲基CpG结合蛋白2）与两个主要 神经发育障碍：RETT综合征（RTT），由MECP2的功能丧失突变引起，并且 MECP2复制综合征（MDS），由MECP2过多引起。 RTT是最常见的遗传之一 女性智力残疾的原因，而（MDS）是最常见的基因组重排之一 男性。因为MECP2蛋白调节了数千种基因在多个脑中的表达 区域，每种疾病的表型远远超出了智力残疾，影响情绪，运动控制， 和自主函数1。大脑对MECP2的数量非常敏感：仅16％ MECP2水平足以产生类似RETT的症状。这个事实是最重要的挑战 为这些疾病开发了有希望的疗法：通过增加RTT的过度射击治疗 MECP2水平过多会导致MDS； MDS中抑制MECP2水平过多会导致RTT。避免 简单地将一组使人衰弱的症状交换为另一种症状，我们需要可靠的方法来测量治疗 响应并评估我们是否正在管理正确的剂量。 人性化小鼠的临床前研究令人信服地证明了反义寡核苷酸 （ASO）可以降低MECP2水平并逆转MDS表型；最近的工作确定了激酶和 调节MECP2稳定性的磷酸酶，同样在小鼠中产生良好的结果。这些选项都非常 有希望，但是我们如何测量患者的MECP2水平？ MECP2是一种核染色质蛋白 这在大脑中非常高的水平表达，在该水平无法进行直接测量。我们有 因此，一直在寻找与MECP2水平相关但可以在血液中测量的其他分子 样品或其他相对无创手段。我建议，对于RTT和MD等复杂疾病， 复合生物标志物面板将优于任何单模式措施来判断治疗反应。我们的 初步研究已经确定了两个重要的分子生物标志物，它们跟踪MECP2水平 在老鼠中；我们还有其他几个候选人。因此，这项研究旨在开发一组临床面板 以及将指导治疗努力以防止过度或不足的分子生物标志物 疾病。德克萨斯州儿童医院的患者人数最多 因此，我们有很好的位置来完成1）制定MD的结果度量； 2）将表型与 XQ28基因座的基因组结构； 3）在人类分子生物标志物中验证随着变化的跟踪 在小鼠的MECP2水平中。完成这三个目标将为ASO的临床试验奠定基础 MD和铺平了涉及其他等位基因疾病的研究途径，涉及过多或太少 相同的基因产物。