Reading Frame Correction for the Treatment of Batten Disease

CLN3Batten病是一种致命性溶酶体储存障碍(LSD)，由常染色体隐性突变引起 在CLN3中。这种疾病从儿童早期的视力丧失发展到癫痫发作、运动能力下降、认知能力下降 残疾和痴呆症，典型的预期寿命为15-30岁。CLN3蝙蝠没有治愈方法 唯一可用的治疗方法可以解决一些疾病症状，但不能延缓疾病的进展。这个 由于缺乏对CLN3巴顿的了解，有效治疗CLN3巴顿的发现一直受到阻碍 蛋白质的功能和导致神经退化的潜在机制。这项提议的目标是 测试使用反义寡核苷酸(ASO)的CLN3 BATTEN的治疗方法， 阐明这种疾病的神经退行性变的机制，将为研究和发现有效的 巴顿病和其他LSD的治疗。大多数CLN3Batten病例是由外显子7缺失引起的 和8(Cln3Δ78)，导致开放阅读框移位和提前终止密码子。我们 用ASOS重定向前Δ剪接并纠正CLN3基因78mR NA阅读框架的假设 将部分恢复蛋白质功能，并对CLN3巴顿病有治疗作用。我们的预赛 研究结果支持了我们的假设，表明恢复CLN3Δ78阅读框可以缓解功能障碍 在细胞和动物模型中都与疾病有关。我们将在提议的项目中检验我们的假设 为了1)比较野生型和新的CLN3亚型的功能，2)开发一种方法 利用ASO增加CLN3Δex78亚型，3)利用人类评估ASO治疗CLN3Batten病的疗效 细胞系以及小鼠和猪的CLN3BATTEN病模型。总而言之，这项研究将使我们 为了更好地了解CLN3蛋白的功能以及ASOS在治疗CLN3Batten病中的作用。

CLN3 Batten disease is a fatal lysosomal storage disorder (LSD) resulting from autosomal recessive mutations in CLN3. The disease progresses from vision loss in early childhood to seizures, motor decline, cognitive disability and dementia, with a typical life expectancy of 15-30 years of age. There is no cure for CLN3 Batten and the only treatments available address some disease symptoms, but do not delay disease progression. The discovery of an effective treatment for CLN3 Batten has been hindered by a lack of understanding of the protein's function and the underlying mechanisms leading to neurodegeneration. The goal of this proposal is to test a therapeutic approach for CLN3 Batten that employs antisense oligonucleotides (ASOs) and in so doing, elucidate mechanisms of neurodegeneration in this disease that will inform research and discovery of effective treatments for Batten diseases and other LSDs. Most cases of CLN3 Batten are caused by deletion of exons 7 and 8 (CLN3Δ78), which results in an open reading frame shift and a premature termination codon. We hypothesize that using ASOs to redirect pre-mRNA splicing and correct the reading frame of CLN3Δ78 mRNA will partially restore protein function and have a therapeutic effect in CLN3 Batten disease. Our preliminary findings support our hypothesis, demonstrating that restoring the CLN3Δ78 reading frame alleviates dysfunction associated with disease in both cell and animal models. We will test our hypothesis in the proposed project with the aims to 1) compare the function of the wild type and novel CLN3 isoforms, 2) develop an approach using ASOs to increase CLN3Δex78 isoforms, 3) assess ASO treatments for CLN3 Batten disease using human cell lines as well as mouse and 4) porcine models of CLN3 Batten disease. Collectively, this study will allow us to better understand the function of the CLN3 protein and the utility of ASOs in treating CLN3 Batten disease.