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（SCA 7）是一种常染色体显性遗传疾病，导致视网膜变性的锥-杆营养不良形式。SCA 7患者遗传的突变是共济失调蛋白-7基因中的CAG /多聚谷氨酰胺（polyQ）重复扩增。SCA 7突变导致产生毒性polyQ-扩增的共济失调蛋白-7。由于毒性基因产物的表达驱动SCA 7和相关polyQ病症中的所有后续疾病病理学，因此这些疾病的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，我们提出了一个翻译研究计划，旨在产生SCA 7视网膜变性的治疗药物。我们将采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（阿索）敲低，来实现共济失调蛋白-7的“基因沉默”。为了实现这一转化研究计划的目标，我们已经建立了学术-工业合作伙伴关系。对于阿索敲除，我们将与ISIS制药公司合作，该公司专门从事阿索生产，已成功开发出用于CMV视网膜炎的阿索疗法。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的研究小组已经开发出准确重现在人类SCA 7患者中观察到的视锥-视杆营养不良表型的小鼠模型，并使用类似的SCA 7基因敲入小鼠模型，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疗效。如果我们的临床前试验工作表明，共济失调蛋白7基因沉默是一种安全有效的治疗SCA 7视网膜变性的方法，那么我们将在该项目的下一阶段继续进行优化和IND研究，作为在人类SCA 7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.