Developing a novel microRNA-mediated therapeutic approach for 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。

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.