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

基本信息

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
项目类别：
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

项目摘要

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）与两个主要蛋白相关神经发育障碍：Rett 综合征 (RTT)，由 MeCP2 功能丧失突变引起，以及 MECP2 重复综合征 (MDS)，由过多的 MeCP2 引起。 RTT 是最常见的遗传因素之一导致女性智力障碍的原因，而（MDS）是女性中最常见的基因组重排之一男性。因为 MeCP2 蛋白调节多个大脑中数千个基因的表达在不同地区，每种疾病的表型远远超出智力障碍，影响情绪、运动控制、和自主功能1。大脑对 MeCP2 的数量极其敏感：仅下降 16% MeCP2 水平足以产生类似 Rett 的症状。这一事实对大多数人来说都是一个显着的挑战针对这些疾病正在开发有前景的疗法：通过增加 RTT 的治疗稍微过度 MeCP2水平过高会引起MDS；在 MDS 中过度抑制 MeCP2 水平会导致 RTT。为了避免只是将一组使人衰弱的症状换成另一组，我们需要可靠的方法来衡量治疗反应并评估我们是否服用了正确的剂量。人源化小鼠的临床前研究令人信服地证明，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 稳定性的磷酸酶在小鼠中也取得了良好的效果。这些选项都非常有希望，但我们如何测量患者的 MeCP2 水平呢？ MeCP2 是一种核染色质结合蛋白它在大脑中表达水平非常高，无法直接测量。我们有因此一直在寻找与 MeCP2 水平相关但可在血液中测量的其他分子样本或其他相对无创的手段。我建议，对于RTT和MDS这样的复杂疾病，复合生物标志物组在判断治疗反应方面将优于任何单一方式的测量。我们的初步研究已经确定了两个追踪 MeCP2 水平的重要分子生物标志物在小鼠中；我们还有几位其他候选人。因此，本研究旨在开发一组临床和分子生物标志物，将指导治疗工作，以防止这些疾病的过度或治疗不足疾病。德克萨斯儿童医院拥有全国最多的 RTT 和 MDS 患者群体，因此，我们有能力实现以下目标： 1) 制定 MDS 的结果衡量标准； 2) 将表型与 Xq28位点的基因组结构； 3) 在人体中验证跟踪变化的分子生物标志物小鼠 MeCP2 水平。完成这三个目标将为 ASO 的临床试验奠定基础 MDS 并为涉及其他等位基因疾病（涉及过多或过少）的研究铺平道路相同的基因产物。