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MicroRNA site-blocking oligonucleotides as a novel therapy for neurodevelopmental disorders

MicroRNA 位点阻断寡核苷酸作为神经发育障碍的新型疗法

基本信息

批准号：
10302244
负责人：
Benjamin Lears Prosser
金额：
$ 47.49万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10302244
关键词：
3&apos Untranslated Regions Affect Antisense Oligonucleotides Binding Binding Sites Bioinformatics Biological Assay Birth Blood specimen Brain CRISPR/Cas technology Cells Child Congenital Abnormality DNA DNA Sequence Alteration Data Disease Encephalopathies Epilepsy Gene Expression Gene Silencing Genes Genetic Genetic Predisposition to Disease Goals Human Intellectual functioning disability Lead Light Mediating Messenger RNA MicroRNAs Mutation NF1 gene Neurodevelopmental Disorder Neurons Oligonucleotides Pathogenicity Patients Proteins Reporter Repression Research SCN8A gene Site Small RNA Source System Testing Therapeutic Therapeutic Effect Transcript Untranslated RNA Up-Regulation Variant Walking Work base behavioral impairment brain tissue cohort dravet syndrome first-in-human gene function gene interaction gene repression genetic variant high throughput screening in silico induced pluripotent stem cell interest loss of function motor impairment novel novel therapeutics preclinical efficacy predictive tools prevent protein expression restoration screening stable cell line symptom treatment targeted treatment transcriptome

项目摘要

Project Summary Neuro-developmental disorders (NDD) are often caused by genetic mutations that lead to haploinsufficiency, or a loss-of-gene function. Mutations that cause haploinsufficiency of neurodevelopmental genes affect over 200,000 births each year, and commonly result in congenital malformations, intellectual disability, epilepsy and motor and behavioral impairments. While symptomatic treatments exist, for most conditions there are no treatments that directly correct the reduced levels of the haploinsufficient gene. Recent research by our group and others has revealed that many NDD-causing genes are normally under active repression by microRNAs, small, non-coding RNAs that function in gene silencing. This raises the possibility of removing this microRNA “brake” to increase gene expression and help restore normal function in NDD haploinsufficiency. We hypothesize that the expression of downregulated genes can be restored through steric-blocking antisense oligonucleotides (ASO) that specifically disrupt gene repression by microRNAs. Our preliminary data support this hypothesis and demonstrate that ASOs that prevent a particular microRNA from binding to STXBP1 (a common NDD-causing gene) robustly upregulate gene and protein expression. We propose a novel pipeline to systematically develop ASOs to treat genetic NDD. First, we will use bioinformatic and wet lab experimental approaches to identify and validate microRNAs that potently repress leading NDD-causing genes. Next, we will use a high-throughput microRNA reporter assays to screen ASOs that can relieve this microRNA-mediated gene repression. Third, we will take lead ASOs identified from the high-throughput screen and test them on neurons derived from patients with genetically-defined NDD to determine if they can rescue gene expression and function. Together, this work will establish pre-clinical efficacy for an ASO-based therapy targeting microRNAs to treat neurodevelopmental disorders arising from haploinsufficiency, and lay the groundwork for first-in-human applications.

项目摘要神经发育障碍（NDD）通常由导致单倍不足的基因突变引起，或基因功能缺失导致神经发育基因单倍不足的突变影响了每年有20万名新生儿出生，通常会导致先天畸形，智力残疾，癫痫和运动和行为障碍虽然存在对症治疗，但对于大多数情况，直接纠正单倍不足基因水平降低的治疗。我们小组最近的研究和其他人已经揭示了许多导致NDD的基因通常受到microRNA的积极抑制，在基因沉默中起作用的小的非编码RNA。这就增加了去除这种微小RNA的可能性， “刹车”增加基因表达，帮助恢复NDD单倍不足的正常功能。我们假设下调基因的表达可以通过空间阻断反义寡核苷酸恢复， (ASO)特异性破坏microRNA对基因的抑制。我们的初步数据支持这一假设，证明了阻止特定microRNA与STXBP1（一种常见的引起NDD的基因）结合的ASO，基因）稳健地上调基因和蛋白质表达。我们提出了一个新的管道，系统地开发用于治疗遗传性NDD的ASO。首先，我们将使用生物信息学和湿实验室实验方法来识别和验证有效抑制导致NDD基因的microRNA。接下来，我们将使用高通量 microRNA报告基因测定以筛选可以缓解这种microRNA介导的基因抑制的ASO。三是将从高通量筛选中识别出主要的ASO，并在来自患者的神经元上进行测试用基因定义的NDD来确定它们是否能拯救基因表达和功能。在一起，这项工作将建立基于ASO的靶向microRNA治疗神经发育的临床前疗效由单倍不足引起的疾病，并为首次在人类中的应用奠定基础。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mapping PTBP2 binding in human brain identifies SYNGAP1 as a target for therapeutic splice switching.

DOI：
10.1038/s41467-023-38273-3
发表时间：
2023-05-06
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Dawicki-McKenna, Jennine M.;Felix, Alex J.;Waxman, Elisa A.;Cheng, Congsheng;Amado, Defne A.;Ranum, Paul T.;Bogush, Alexey;Dungan, Lea V.;Maguire, Jean Ann;Gagne, Alyssa L.;Heller, Elizabeth A.;French, Deborah L.;Davidson, Beverly L.;Prosser, Benjamin L.
通讯作者：
Prosser, Benjamin L.

Base editing the synapse: Modeling a complex neurological disorder in non-human primates.

突触碱基编辑：模拟非人类灵长类动物的复杂神经系统疾病。