美国罗莎琳德富兰克林医科大学Michelle L. Hastings团队，研究了反义寡核苷酸在CLN3巴顿病小鼠模型中的治疗效果。这一研究成果发表在2020年7月27日出版的《自然-医学》上。

研究人员表明具有CLN3的7和8外显子缺失（CLN3^{Δex7/ 8}）的小鼠可使用反义寡核苷酸（ASO）进行有效治疗，该反义寡核苷酸可诱导外显子跳跃以恢复开放阅读框。单次靶向外显子5的ASO治疗可诱导显著的外显子跳跃并能维持超过一年，其改善了小鼠运动协调性、降低了Cln3^{Δex7/ 8}小鼠的组织病理学，并增加了该疾病模型小鼠的存活率。ASOs还诱导来自CLN3 巴顿病患者细胞系中的外显子跳跃。

该发现表明，基于ASO的阅读框校正可作为一种治疗CLN3巴顿病的方法，并可使用类似的策略拓宽ASO在治疗其他疾病中的应用前景。

据了解，CLN3 巴顿病是一种由CLN3突变引起的常染色体隐性遗传、神经退行性、溶酶体贮存病，CLN3编码溶酶体膜蛋白。目前尚无针对这种疾病的治疗方法，该疾病在25,000名新生儿中就有1例。巴顿病在儿童早期就出现症状，通常在20-30岁时致命。大多数患有CLN3 巴顿病的患者均缺失CLN3^{Δex7/ 8}，从而产生易码突变。

附：英文原文

Title: Therapeutic efficacy of antisense oligonucleotides in mouse models of CLN3 Batten disease

Author: Jessica L. Centa, Francine M. Jodelka, Anthony J. Hinrich, Tyler B. Johnson, Joseph Ochaba, Michaela Jackson, Dominik M. Duelli, Jill M. Weimer, Frank Rigo, Michelle L. Hastings

Issue&Volume: 2020-07-27

Abstract: CLN3 Batten disease is an autosomal recessive, neurodegenerative, lysosomal storage disease caused by mutations in CLN3, which encodes a lysosomal membrane protein1,2,3. There are no disease-modifying treatments for this disease that affects up to 1 in 25,000 births, has an onset of symptoms in early childhood and typically is fatal by 20–30 years of life4,5,6,7. Most patients with CLN3 Batten have a deletion encompassing exons 7 and 8 (CLN3ex7/8), creating a reading frameshift7,8. Here we demonstrate that mice with this deletion can be effectively treated using an antisense oligonucleotide (ASO) that induces exon skipping to restore the open reading frame. A single treatment of neonatal mice with an exon 5-targeted ASO-induced robust exon skipping for more than a year, improved motor coordination, reduced histopathology in Cln3ex7/8 mice and increased survival in a new mouse model of the disease. ASOs also induced exon skipping in cell lines derived from patients with CLN3 Batten disease. Our findings demonstrate the utility of ASO-based reading-frame correction as an approach to treat CLN3 Batten disease and broaden the therapeutic landscape for ASOs in the treatment of other diseases using a similar strategy.

DOI: 10.1038/s41591-020-0986-1

Source: https://www.nature.com/articles/s41591-020-0986-1