Investigating a candidate therapeutic for Rett Syndrome

研究雷特综合征的候选疗法

基本信息

批准号：
9814949
负责人：
JEANNIE T LEE
金额：
$ 79.58万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9814949
关键词：
Address Affect Age Age-Months Alleles Animal Model Animal Testing Antisense Oligonucleotides Biology Brain Cell Line Cell model Cells Chromatin Chromosomes Clinic Communities DNA Data Decitabine Disease Disease model Dose Drug Industry Drug toxicity Epilepsy Evaluation Female Foundations Fragile X Syndrome Funding Genes Genetic Genetic Diseases Goals Grant In Vitro Inherited Injections Life Life Expectancy Link Longitudinal Studies Methods Methyl-CpG-Binding Protein 2 Modality Modeling Morbidity - disease rate Mus Mutation Neuraxis Neurodevelopmental Disorder Onset of illness Outcome Patients Penetrance Pharmaceutical Preparations Pharmacology Phenocopy Phenotype Plant Roots Proteins Regimen Reporter Research Rett Syndrome Scientist Secure Seeds Seizures Severity of illness Symptoms Syndrome Testing Therapeutic Index Toxic effect Toxicology United States National Institutes of Health Untranslated RNA Up-Regulation Work X Chromosome X Inactivation acute toxicity autism spectrum disorder disease phenotype drug candidate drug testing gene product genome-wide girls in vivo in vivo evaluation industry partner interest lead candidate lead optimization male mortality mouse model nervous system disorder neuron development new technology novel novel therapeutics pharmacokinetics and pharmacodynamics preclinical development prototype restoration small molecule standard of care success synergism therapeutic candidate treatment strategy

项目摘要

The X-chromosome harbors hundreds of disease genes whose associated diseases predominantly affect males. However, a subset — including neurodevelopmental disorders, Rett (RTT), Fragile X (FXS), and CDKL5 Syndromes — also or only affects females. Autism is a frequent manifestation. Because female cells carry a second copy of the X-chromosome, an emerging treatment strategy has been to reawaken the healthy allele on this inactive X (Xi) to reverse disease symptoms. An obstacle has been that the Xi is subject to a very robust silencing mechanism and, for decades, it was thought that Xi-reactivation would not be possible. However, recent work from our lab and other groups indicates that Xi reactivation can be achieved. We have been focusing on Rett Syndrome (RTT) and leveraging our understanding of XCI biology to develop Xi- reactivating drugs. RTT is a severe neurodevelopmental disorder that affects ~1:10,000 girls throughout the world. Affected girls inherit one defective copy of methyl-CpG-binding protein 2 (MECP2), a chromatin- associated gene product that is crucial for neuronal development. RTT girls are born normal and develop normally for the first few months of life, but begin to regress between 6-12 months of age. RTT is associated with severe autism and seizures, and is one of the most debilitating genetic disorders. There is no disease- specific treatment at present, as the standard of care treats only general symptoms. In a landmark discovery of 2007, scientists demonstrated in a mouse model that restoring MECP2 expression after onset of RTT symptoms reverses the neurological disease. MECP2 restoration is therefore of major interest to the pharmaceutical industry. Because MECP2 is an X-linked gene subject to X-inactivation and nearly all patients are heterozygous for the MECP2 gene, every affected girl carries a good copy of MECP2 on the Xi of her sick cells. Our goal is to unlock the Xi and restore expression of MECP2. With seed funding from foundations and an expired/non-renewable NIH grant, my lab has worked on this problem for the past 7 years. Critical for testing Xi-reactivating drugs is a female mouse model for RTT, because existing Mecp2+/- female mice have variable disease penetrance, only a mild disease later in life, and are therefore not suitable as a model for the Xi-reactivation platform. We have now created a new female RTT mouse model that carries wildtype Mecp2 on the Xi, phenocopies the severe disease seen in male RTT mice, and is therefore an ideal model for testing Xi- reactivating drug candidates. Moreover, we have identified a first-in-class, mixed modality drug capable of reactivating MECP2 up to 30,000-fold in a cellular model. The goals of our proposed research are (i) optimization and preclinical development of the lead candidate in a mouse model, (ii) PK/PD studies and longitudinal evaluation of potential drug toxicities in vivo, and (iii) determination of efficacy in the new disease- relevant animal model. By the end of the 5-year project, we hope to secure proof-of-concept for in vivo MECP2 upregulation and phenotypic rescue, and establish industry partnerships to develop the drug for the clinic.

X染色体具有数百种相关疾病的疾病基因，主要影响男性。但是，一个子集 - 包括神经发育障碍，RETT（RTT），脆弱的X（FXS）和 CDKL5综合征 - 或仅影响女性。自闭症通常是一种表现。因为女性细胞携带第二份X染色体的副本，新兴的治疗策略是恢复健康在这种无效X（XI）上的等位基因逆转疾病症状。一个障碍是XI受到非常强大的沉默机制，几十年来，人们认为XI反应是不可能的。但是，我们实验室和其他小组的最新工作表明可以实现XI重新激活。我们有我们专注于RETT综合征（RTT），并利用我们对XCI生物学的理解来发展XI- 重新激活药物。 RTT是一种严重的神经发育障碍，在整个过程中影响〜1：10,000个女孩世界。受影响的女孩继承了一个有缺陷的甲基-CPG结合蛋白2（MECP2）的副本，一种染色质 - 相关的基因产物对于神经元发育至关重要。 RTT女孩天生正常并发展通常在生命的头几个月，但在6-12个月大的时候开始退缩。 RTT关联患有严重的自闭症和癫痫发作，是最令人衰弱的遗传疾病之一。没有疾病 - 目前，特定的治疗方法是护理标准仅治疗一般症状。在地标发现在2007年，科学家在小鼠模型中证明了RTT发作后恢复MECP2的表达症状扭转了神经疾病。因此，MECP2恢复是主要兴趣制药行业。因为MECP2是受X灭活的X连锁基因，几乎所有患者对于MECP2基因是杂合的，每个受影响的女孩都在她病的XI上携带MECP2的副本细胞。我们的目标是解锁XI并恢复MECP2的表达。从基金会的种子资金和我的实验室是过期/不可再生的NIH赠款，在过去的7年中一直致力于此问题。至关重要测试XI反应药物是RTT的雌性小鼠模型，因为现有的MECP2 +/-雌鼠具有可变疾病的外观，仅在以后的生活中是一种温和的疾病，因此不适合作为模型 XI反应平台。现在，我们创建了一种新的女性RTT鼠标模型，该模型在 Xi，近代的雄性RTT小鼠中发现的严重疾病，因此是测试XI-XI的理想模型重新激活候选药物。此外，我们已经确定了一种能够在细胞模型中重新激活MECP2高达30,000倍。我们拟议的研究的目标是（i）在小鼠模型中，（ii）PK/PD研究中的铅候选者的优化和临床前发展对体内潜在药物毒性的纵向评估，以及（iii）确定新疾病的效率 - 相关动物模型。到5年项目结束时，我们希望确保体内MECP2的概念证明上调和表型救援，并建立行业伙伴关系以开发诊所的药物。