Developing a novel microRNA-mediated therapeutic approach for SCA6

开发一种新型 microRNA 介导的 SCA6 治疗方法

• 批准号: 9402209
• 负责人: Christopher Manuel Gomez
• 金额: $ 24.3万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9402209
• 关键词: Acute; Adenoviruses; Adult; Adverse effects; Affect; Age of Onset; Alleles; Ataxia; Atrophic; Base Sequence; CAG repeat; Calcium Channel; Cell Maturation; Cells; Cerebellar Diseases; Cerebellar cortex structure; ChIP-seq; Child; Clinical; Data; Development; Disease; Effectiveness; Electrophysiology (science); Ensure; Gene Expression; Gene Targeting; Genes; Goals; Histologic; Human; In Vitro; Inherited; Injection of therapeutic agent; Internal Ribosome Entry Site; Intravenous; Intraventricular; Ion Channel; Kinetics; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular Profiling; Mus; Mutation; Neonatal; Neurodegenerative Disorders; Open Reading Frames; Parents; Patients; Physiological; Play; Pre-Clinical Model; Precipitation; Proteins; Purkinje Cells; Recombinants; Regulator Genes; Role; Route; Spinocerebellar Ataxias; Synapses; Therapeutic; Thinness; Toxic effect; Transgenes; Transgenic Mice; Transgenic Model; Translating; Translational Repression; Translations; Type 6 Spinocerebellar Ataxia; Virus; adeno-associated viral vector; base; behavior measurement; cell cortex; compare effectiveness; gene therapy; in vivo; in vivo Model; induced pluripotent stem cell; insight; intravenous administration; mRNA Transcript Degradation; mouse model; mutant; novel; polyglutamine; prevent; protein expression; therapeutic target; transcription factor; transcriptome sequencing; voltage

ABSTRACT Spinocerebellar ataxia type 6 (SCA6) is an incurable hereditary degenerative ataxic disease passed from parent to child. We have developed a novel, microRNA-based gene therapy approach to inhibit expression the disease-causing protein, alpha1ACT made by the gene CACNA1A. This approach, which relies on an adenovirus to deliver the micro RNA, spares the other critical CACNA1A protein, alpha1A calcium channel subunit, although it appears to suppress both the disease-causing and normal alpha1ACT proteins. Here in Aim 1 we propose to expand on our initial study that inhibited a hyper acute neonatal mouse of SCA6 by comparing two different routes (intraventricular and intravenous) of administration of the adenovirus- microRNA, for effectiveness in blocking the hyperacute mouse model and a new BAC-based transgenic mouse model. In Aim 2 we will use a mouse CACNA1A mutant and a novel transgenic mouse model expressing normal alpha1ACT to prove that suppression of normal alpha1ACT is safe in adult mice, paving the way to safely envision a similar approach in patients with SCA6.

摘要 脊髓小脑共济失调6型（SCA6）是一种无法治愈的遗传性退行性共济失调疾病， 从父母到孩子我们已经开发了一种新的基于microRNA的基因治疗方法，以抑制 致病蛋白，由基因CACNA1A产生的α 1ACT。这种方法依赖于 腺病毒可以递送微小RNA，而不需要另一种关键的CACNA 1A蛋白质，即α 1A钙通道 亚基，虽然它似乎抑制致病和正常的α 1 ACT蛋白。 在目标1中，我们建议扩展我们的初步研究，即抑制SCA6的超急性新生小鼠 通过比较两种不同的腺病毒给药途径（脑室内和静脉内）， microRNA，用于有效阻断超急性小鼠模型和新的基于BAC的转基因小鼠 模型 在目标2中，我们将使用小鼠CACNA1A突变体和表达正常 alpha1ACT，以证明在成年小鼠中抑制正常的alpha1ACT是安全的，为安全地 设想在SCA6患者中采用类似的方法。