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Developing a novel microRNA-mediated therapeutic approach for SCA6

开发一种新型 microRNA 介导的 SCA6 治疗方法

基本信息

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
项目类别：
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

项目摘要

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.

摘要脊髓小脑性共济失调6型(Sca6)是一种遗传性共济失调疾病。从父母到孩子。我们已经开发了一种新的、基于microRNA的基因治疗方法来抑制致病蛋白，由CACNA1a基因组成。这种方法依赖于腺病毒传递微小RNA，省去了另一种关键的CACNA1a蛋白，即alpha1A钙通道亚基，尽管它似乎抑制致病和正常的α1ACT蛋白。在这里的目标1中，我们建议扩展我们最初的研究，该研究抑制了一只超急性新生小鼠的SCA6 通过比较两种不同的腺病毒给药途径(脑室和静脉给药)- 阻断超急性小鼠模型及新型BAC转基因小鼠的效果模特。在目标2中，我们将使用一个小鼠CACNA1a突变体和一个新的表达正常的转基因小鼠模型 Alpha1ACT证明抑制正常Alpha1ACT对成年小鼠是安全的，为安全地设想在SCA6患者中采用类似的方法。