Reading Frame Correction for the Treatment of Batten Disease

CLN 3 Batten病是由常染色体隐性突变引起的致死性溶酶体贮积症（LSD） 在CLN 3中。该疾病从儿童早期的视力丧失发展为癫痫发作、运动能力下降、认知能力下降、认知障碍、认知 残疾和痴呆，典型的预期寿命为15-30岁。CLN 3 Batten无法治愈 仅有的治疗方法可以解决一些疾病症状，但不能延缓疾病进展。的 对CLN 3 Batten的有效治疗的发现受到缺乏对CLN 3治疗的理解的阻碍。 蛋白质的功能和导致神经变性的潜在机制。本提案的目的是 测试采用反义寡核苷酸（ASO）的CLN 3 Batten的治疗方法， 阐明这种疾病的神经变性机制，将为研究和发现有效的 治疗巴顿病和其他迷幻药大多数CLN 3 Batten病例是由外显子7缺失引起的 和8（CLN 3 Δ78），这导致开放阅读移码和提前终止密码子。我们 假设使用ASO重定向CLN 3 Δ78 mRNA的前体剪接并校正其阅读框 将部分恢复蛋白质功能，并对CLN 3 Batten病有治疗作用。我们的初步 研究结果支持我们的假设，表明恢复CLN 3 Δ78阅读框架会导致功能障碍 在细胞和动物模型中与疾病相关。我们将在拟议的项目中检验我们的假设 目的是1）比较野生型和新型CLN 3同种型的功能，2）开发一种方法， 使用ASO增加CLN 3 Δ ex 78同种型，3）使用人类评估CLN 3巴滕病的阿索治疗 细胞系以及CLN 3 Batten病的小鼠和4）猪模型。总的来说，这项研究将使我们 更好地了解CLN 3蛋白的功能和ASO在治疗CLN 3 Batten病中的效用。

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.