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

描述（由申请人提供）：脊髓小脑性共济失调7型（SCA7）是一种常染色体显性遗传病，导致锥杆营养不良形式的视网膜变性。由SCA7患者遗传的突变是在ataxin-7基因中CAG / polyQ重复扩增。SCA7突变导致产生有毒的聚q扩增ataxin-7蛋白。由于有毒基因产物的表达驱动了SCA7和相关多q疾病的所有后续疾病病理，因此这些疾病最有吸引力的治疗范式是终止突变基因产物的表达。在这里，我们提出了一个转化研究计划，旨在产生治疗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毒性蛋白表达的治疗策略——反义寡核苷酸（ASO）敲除，来追求ataxin-7“基因沉默”。为了实现这个转化研究项目的目标，我们建立了一个学术-工业合作伙伴关系。对于ASO敲除，我们将与专门生产ASO的ISIS制药公司合作，该公司已经成功开发了一种针对巨细胞病毒性视网膜炎的ASO疗法。通过与ISIS合作，我们已经在试点研究中找到了有效抑制ataxin-7的线索。由于PI的小组已经开发出小鼠模型，准确地概括了在人类SCA7患者中观察到的锥杆营养不良表型，并且已经使用了类似的SCA7敲入小鼠模型，我们将采用一系列行为，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表明ataxin7基因沉默是一种安全有效的治疗SCA7视网膜变性的方法，那么我们将在本项目的下一阶段进行先导优化和IND-enabling研究，作为在人类SCA7患者中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.