Antisense oligonucleotide knock-down of ataxin-7 in a SCA7 mouse model

描述(申请人提供)：脊髓小脑性共济失调7型(SCA7)是一种常染色体显性遗传性疾病，导致视锥-视杆细胞营养不良形式的视网膜变性。SCA7患者遗传的突变是ataxin-7基因中CAG/多聚谷氨酰胺(PolyQ)重复扩增。SCA7突变导致产生一种有毒的多Q扩展的ataxin-7蛋白。由于有毒基因产物的表达驱动了SCA7和相关的PolyQ疾病的所有后续疾病病理，因此对这些疾病最有吸引力的治疗范例是终止突变基因产物的表达。在这里，我们提出了一个转译研究计划，旨在生产治疗SCA7视网膜变性的药物。我们将使用一种已经成功应用于降低有毒蛋白质表达的治疗策略-反义寡核苷酸(ASO)敲除，来实现ataxin-7“基因沉默”。为了实现这一翻译研究项目的目标，我们建立了学术和产业合作伙伴关系。对于ASO的击倒，我们将与ISIS制药公司合作，这是一家专门生产ASO的公司，已经成功地开发了一种治疗CMV视网膜炎的ASO疗法。与ISIS合作，我们已经在试点研究中产生了有效击倒ataxin-7的线索。由于Pi的团队已经开发出准确概括在人类SCA7患者中观察到的锥视杆营养不良表型的小鼠模型，并使用了类似的SCA7敲入小鼠模型，因此我们将使用一系列行为、组织学和分子研究来确定这些治疗策略在临床前试验中的有效性。如果我们的临床前试验工作显示，ataxin7基因沉默是治疗SCA7视网膜变性的安全有效的方法，那么我们将在该项目的下一阶段继续领导优化和启用IND的研究，作为在人类SCA7患者上进行临床试验的前奏。

DESCRIPTION (provided by applicant): Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant disorder that results in a cone- rod dystrophy form of retinal degeneration. The mutation inherited by SCA7 patients is a CAG / polyglutamine (polyQ) repeat expansion in the ataxin-7 gene. The SCA7 mutation results in the production of a toxic polyQ-expanded ataxin-7 protein. Since the expression of the toxic gene product drives all subsequent disease pathology in SCA7 and related polyQ disorders, the most attractive therapeutic paradigm for these diseases is to terminate the expression of the mutant gene product. Here we propose a translational research program intended to yield therapeutic agents for SCA7 retinal degeneration. We will pursue ataxin-7 "gene silencing" using a therapeutic strategy that has already been successfully applied to achieve reduced expression of a toxic protein: antisense oligonucleotide (ASO) knock-down. To achieve the goals of this translational research program, we have created an academic-industrial partnership. For ASO knock-down, we will work with ISIS Pharmaceuticals, a company that specializes in ASO production, having successfully developed an ASO therapy for CMV retinitis. Working with ISIS, we have already generated leads that effectively knock-down ataxin-7 in pilot studies. As the PI's group has developed mouse models that accurately recapitulate the cone-rod dystrophy phenotype observed in human SCA7 patients, and has worked with a similar SCA7 knock-in mouse model, we will employ a series of behavioral, histological and molecular studies to determine the efficacy of these treatment strategies in preclinical trials. If our preclinical trial work reveals that ataxin7 gene silencing is a safe and effective therapy for SCA7 retinal degeneration, then we will proceed to lead optimization and IND-enabling studies in the next stage of this project, as a prelude to a clinical trial in human SCA7 patients.