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染色体含有数百个疾病基因，其相关疾病主要影响然而，有一个子集——包括神经发育障碍、Rett (RTT)、Fragile X (FXS) 和 CDKL5 综合征——也或仅影响女性自闭症是一种常见的表现，因为女性细胞。携带第二个 X 染色体副本，一种新兴的治疗策略是重新唤醒健康这种不活跃的 X (Xi) 上的等位基因逆转疾病症状的一个障碍是 Xi 受到非常大的影响。几十年来，人们一直认为习近平不可能重新激活。然而，我们实验室和其他小组最近的工作表明，Xi 的重新激活是可以实现的。一直专注于 Rett 综合征 (RTT) 并利用我们对 XCI 生物学的理解来开发 Xi- RTT 是一种严重的神经发育障碍，影响着大约 1:10,000 的女孩。受影响的女孩继承了甲基 CpG 结合蛋白 2 (MECP2) 的一个有缺陷的副本，这是一种染色质- 对 RTT 女孩的神经发育至关重要的相关基因产物出生时和发育正常。通常在出生后的最初几个月，RTT 会在 6-12 个月时开始消退。患有严重的自闭症和癫痫症，是最使人衰弱的遗传性疾病之一。目前，特异性治疗作为护理标准仅治疗一般症状，这是一个里程碑式的发现。 2007 年，科学家在小鼠模型中证明，在 RTT 开始后恢复 MECP2 表达因此，MECP2 的恢复对因为 MECP2 是一种 X 连锁基因，几乎所有患者都会遭受 X 失活。是 MECP2 基因杂合子，每个受影响的女孩在她患病的 Xi 上都携带良好的 MECP2 副本我们的目标是利用基金会的种子资金来解锁 Xi 并恢复 MECP2 的表达。一项过期/不可更新的 NIH 拨款，我的实验室在过去 7 年里一直致力于解决这个问题。测试 Xi 重新激活药物是 RTT 的雌性小鼠模型，因为现有的 Mecp2+/- 雌性小鼠具有疾病外显率可变，在以后的生活中只是一种轻微的疾病，因此不适合作为模型 Xi-重新激活平台我们现在创建了一种携带野生型 Mecp2 的新雌性 RTT 小鼠模型。 Xi，表现出雄性 RTT 小鼠中观察到的严重疾病，因此是测试 Xi-的理想模型此外，我们还确定了一种一流的混合模式药物。在细胞模型中重新激活 MECP2 高达 30,000 倍我们提出的研究目标是 (i) 主要候选药物在小鼠模型中的优化和临床前开发，(ii) PK/PD 研究和评估潜在的药物体内毒性，以及（iii）确定对新疾病的功效- 相关动物模型。在为期 5 年的项目结束时，我们希望获得体内 MECP2 的概念验证。上调和表型拯救，并建立行业合作伙伴关系，为临床开发药物。