Therapeutic potential for Prader-Willi syndrome

普瑞德威利综合征的治疗潜力

• 批准号: 8860216
• 负责人: YONG-HUI JIANG
• 金额: $ 22.46万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8860216
• 关键词: Affect; Angelman Syndrome; Binding; Candidate Disease Gene; Cells; Chimeric Proteins; Chromosomes; Clinical; Collaborations; CpG Islands; Cultured Cells; DNA; DNA Methylation; Data; Defect; Development; Developmental Delay Disorders; Embryo; Epigenetic Process; FDA approved; Fibroblasts; Gene Expression; Genes; Genetic Transcription; Genomic Imprinting; Goals; Health; Hereditary Disease; Histones; Human; Hyperphagia; Hypogonadism; Individual; Lead; Lysine; Measures; Methodology; Modification; Molecular; Molecular Target; Mus; Mutant Strains Mice; National Institute of Mental Health; North Carolina; Pathogenesis; Patients; Pharmaceutical Preparations; Phase; Phenotype; Prader-Willi Syndrome; Preclinical Drug Evaluation; Process; Psychotropic Drugs; Quality of life; Reporting; Repression; SNRPN; Small Nucleolar RNA; Specificity; Testing; Therapeutic; Therapeutic Intervention; Transcript; Universities; Untranslated RNA; Work; chromatin modification; cytotoxicity; disability; dosage; drug candidate; embryonic stem cell; genome-wide; histone methyltransferase; histone modification; imprint; in vivo; inhibitor/antagonist; innovation; insight; interest; mouse model; neurobehavioral disorder; novel; obesity in children; programs; promoter; response; screening; small molecule; small molecule libraries; tool

DESCRIPTION (provided by applicant): Like most genetic disorders, no specific therapeutic intervention targets the specific molecular defect of Prader- Willi syndrome (PWS), a genomic imprinting and neurobehavioral disorder. PWS is caused by paternal deficiency of genes in the chromosome 15q11-q13 region. The corresponding genes in the maternal chromosome are structurally intact, but their transcription is repressed epigenetically. The involvement of epigenetic repression renders PWS as one of the best opportunities to explore molecular therapy. Recent reports indicate SnoRNA, clusters including HBII-85 (SNORD116) between the SNRPN and UBE3A genes, is responsible for key features of PWS including childhood obesity, hypogonadism, hyperphagia, and developmental delay. Epigenetic mechanisms, including DNA methylation and chromatin modifications at the PWS imprinting center region (PWS-ICR), are involved in regulating the paternal-specific expression of genes including SNRPN and SnoRNAs in the 15q11-q13 region. The imprinting domain in the 15q11-q13 region is highly conserved in mice. The expression of SnoRNA clusters is processed from continuous transcripts initiated from the PWS-ICR/promoter bound CpG island of SNRPN. DNA methylation can activate the expression of the SNRPN gene from the silent maternal chromosome in cultured cells of PWS patients and mouse models, but its clinical utility is limited by the concern of the genome wide effect of these drugs. These observations, however, strongly support a approach to unsilence/activate the expression of SnoRNAs from maternal chromosome through an epigenetic mechanism. Because the SnoRNAs are non-coding, we propose to use embryonic fibroblasts (MEFs) from mice carrying Snrpn-EGFP fusion protein as screening tool. Drugs that activate the Snrpn-EGFP are expected to have the same impact on the SnoRNAs. In collaboration with Dr. Bryan Roth (Director of NIMH Psychoactive Drug Screening Program), we have completed the first phase screen and identified several candidate drugs. We have showed that a histone methyltransferase inhibitor activated the expression of Snrpn and SnoRNAs from the maternal chromosome in cultured PWS cells. Using the same strategy, Dr. Roth's team also identified a FDA approved drug that activates the Angelman syndrome Ube3a gene from paternal chromosome in vivo. The long term goal of our project is to develop a therapeutic intervention targeted to the specific epigenetic defects of PWS. The central hypothesis is that a small molecule can modulate the epigenetic modification in the PWS-ICR and lead to the activation of the silenced PWS candidate genes from the maternal chromosome. The specific objective is to identify and characterize small molecules that activate the expression of Snrpn and SnoRNAs from the maternal chromosome by performing high-content small molecule screening using maternal Snrpn-EGFP as a marker. The proposed study is significant because it will lead to the development of a therapeutic intervention in PWS and provide the novel insight for molecular mechanism underlying the genomic imprinting.

描述（由申请人提供）：与大多数遗传性疾病一样，没有针对普瑞德-威利综合征（PWS）（一种基因组印记和神经行为障碍）的特定分子缺陷的特定治疗干预措施。 PWS 是由染色体 15q11-q13 区域的父系基因缺陷引起的。母体染色体中的相应基因在结构上是完整的，但它们的转录在表观遗传上受到抑制。表观遗传抑制的参与使得 PWS 成为探索分子治疗的最佳机会之一。最近的报告表明，SnoRNA，即 SNRPN 和 UBE3A 基因之间的 HBII-85 (SNORD116) 簇，与 PWS 的关键特征有关，包括儿童肥胖、性腺功能减退、食欲亢进和发育迟缓。表观遗传机制，包括 PWS 印记中心区域 (PWS-ICR) 的 DNA 甲基化和染色质修饰，参与调节 15q11-q13 区域中 SNRPN 和 SnoRNA 等基因的父系特异性表达。 15q11-q13 区域的印记结构域在小鼠中高度保守。 SnoRNA 簇的表达是从 SNRPN 的 PWS-ICR/启动子结合 CpG 岛起始的连续转录本进行处理的。 DNA甲基化可以激活PWS患者和小鼠模型的培养细胞中沉默母体染色体中SNRPN基因的表达，但由于这些药物的全基因组效应，其临床应用受到限制。然而，这些观察结果强烈支持通过表观遗传机制来沉默/激活母体染色体 SnoRNA 表达的方法。由于 SnoRNA 是非编码的，我们建议使用携带 Snrpn-EGFP 融合蛋白的小鼠胚胎成纤维细胞 (MEF) 作为筛选工具。激活 Snrpn-EGFP 的药物预计会对 SnoRNA 产生相同的影响。我们与 Bryan Roth 博士（NIMH 精神活性药物筛选项目主任）合作，完成了第一阶段筛选并确定了几种候选药物。我们已经证明，组蛋白甲基转移酶抑制剂激活培养的 PWS 细胞中母体染色体的 Snrpn 和 SnoRNA 的表达。使用相同的策略，Roth 博士的团队还发现了一种 FDA 批准的药物，可以在体内激活来自父本染色体的天使综合征 Ube3a 基因。我们项目的长期目标是开发针对 PWS 特定表观遗传缺陷的治疗干预措施。中心假设是小分子可以调节 PWS-ICR 中的表观遗传修饰，并导致母体染色体上沉默的 PWS 候选基因的激活。具体目标是通过使用母体 Snrpn-EGFP 作为标记物进行高内涵小分子筛选，鉴定和表征激活母体染色体 Snrpn 和 SnoRNA 表达的小分子。这项研究意义重大，因为它将促进 PWS 治疗干预的发展，并为基因组印记背后的分子机制提供新的见解。

项目成果

Psychometric properties of the Chinese Parent Version of the Autism Spectrum Rating Scale: Rasch analysis.

• DOI: 10.1177/13623613211004054
• 发表时间: 2021-10
• 期刊: Autism : the international journal of research and practice
• 作者: Yan W;Siegert RJ;Zhou H;Zou X;Wu L;Luo X;Li T;Huang Y;Guan H;Chen X;Mao M;Xia K;Zhang L;Li E;Li C;Zhang X;Zhou Y;Shih A;Fombonne E;Zheng Y;Han J;Sun Z;Jiang YH;Wang Y
• 通讯作者: Wang Y

Potassium channel dysfunction in human neuronal models of Angelman syndrome.

• DOI: 10.1126/science.aav5386
• 发表时间: 2019-12-20
• 期刊: Science (New York, N.Y.)
• 作者: Sun AX;Yuan Q;Fukuda M;Yu W;Yan H;Lim GGY;Nai MH;D'Agostino GA;Tran HD;Itahana Y;Wang D;Lokman H;Itahana K;Lim SWL;Tang J;Chang YY;Zhang M;Cook SA;Rackham OJL;Lim CT;Tan EK;Ng HH;Lim KL;Jiang YH;Je HS
• 通讯作者: Je HS

Chromosomal microarray analysis in clinical evaluation of neurodevelopmental disorders-reporting a novel deletion of SETDB1 and illustration of counseling challenge.

染色体微阵列分析在神经发育障碍临床评估中的应用——报告SETDB1的新缺失并说明咨询挑战

• DOI: 10.1038/pr.2016.101
• 发表时间: 2016-09
• 期刊: Pediatric research
• 影响因子: 3.6
• 作者: Xu Q;Goldstein J;Wang P;Gadi IK;Labreche H;Rehder C;Wang WP;McConkie A;Xu X;Jiang YH
• 通讯作者: Jiang YH

Monogenic mouse models of autism spectrum disorders: Common mechanisms and missing links.

• DOI: 10.1016/j.neuroscience.2015.12.040
• 发表时间: 2016-05-03
• 期刊: Neuroscience
• 影响因子: 3.3
• 作者: Hulbert SW;Jiang YH
• 通讯作者: Jiang YH

Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader-Willi syndrome.

• DOI: 10.1038/nm.4257
• 发表时间: 2017-03
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Kim Y;Lee HM;Xiong Y;Sciaky N;Hulbert SW;Cao X;Everitt JI;Jin J;Roth BL;Jiang YH
• 通讯作者: Jiang YH