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: 10680582
• 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/10680582
• 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; Dedications; Development; Disease; Dose; Drops; Enrollment; Female; Genes; Genetic; Genomics; Genotype; Heme; Human; Intellectual functioning disability; Link; Maps; 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; Syndrome; Texas; Therapeutic; Universities; Visit; Western Blotting; Wild Type Mouse; Work; biomarker identification; biomarker panel; biomarker validation; 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.

摘要

项目成果

Exploring the characteristics and most bothersome symptoms in MECP2 duplication syndrome to pave the path toward developing parent-oriented outcome measures.

• DOI: 10.1002/mgg3.1989
• 发表时间: 2022-08
• 期刊: Molecular genetics & genomic medicine
• 影响因子: 2

Biallelic variants in ADAMTS15 cause a novel form of distal arthrogryposis.

• DOI: 10.1016/j.gim.2022.07.012
• 发表时间: 2022-10
• 期刊: GENETICS IN MEDICINE
• 影响因子: 8.8
• 作者: Boschann, Felix;Cogulu, Muhsin O.;Pehlivan, Davut;Balachandran, Saranya;Vallecillo-Garcia, Pedro;Grochowski, Christopher M.;Hansmeier, Nils R.;Akdemir, Zeynep H. Coban;Prada-Medina, Cesar A.;Aykut, Ayca;Fischer-Zirnsak, Bjorn;Badura, Simon;Durmaz, Burak;Ozkinay, Ferda;Haegerling, Rene;Posey, Jennifer E.;Stricker, Sigmar;Gillessen-Kaesbach, Gabriele;Spielmann, Malte;Horn, Denise;Brockmann, Knut;Lupski, James R.;Kornak, Uwe;Schmidt, Julia
• 通讯作者: Schmidt, Julia

Publisher Correction: Detection of mosaic and population-level structural variants with Sniffles2.

出版商更正：使用 Sniffles2 检测马赛克和群体水平的结构变异。

• DOI: 10.1038/s41587-024-02141-2
• 发表时间: 2024
• 期刊: Nature biotechnology
• 影响因子: 46.9
• 作者: Smolka,Moritz;Paulin,LuisF;Grochowski,ChristopherM;Horner,DominicW;Mahmoud,Medhat;Behera,Sairam;Kalef-Ezra,Ester;Gandhi,Mira;Hong,Karl;Pehlivan,Davut;Scholz,SonjaW;Carvalho,ClaudiaMB;Proukakis,Christos;Sedlazeck,FritzJ
• 通讯作者: Sedlazeck,FritzJ