Therapeutic efficacy of antisense oligonucleotides in mouse models of CLN3 Batten disease.
Therapeutic efficacy of antisense oligonucleotides in mouse models of CLN3 Batten disease.
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DOI：
10.1038/s41591-020-0986-1
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发表时间：
2020-09
期刊：
影响因子：
82.9
通讯作者：
Hastings ML
中科院分区：
文献类型：
--
作者：
Centa JL;Jodelka FM;Hinrich AJ;Johnson TB;Ochaba J;Jackson M;Duelli DM;Weimer JM;Rigo F;Hastings ML
CLN 3 Batten病是由编码溶酶体膜蛋白的CLN 3突变引起的常染色体隐性、神经退行性、溶酶体贮积病。对于这种疾病没有改善疾病的治疗方法，这种疾病影响到25，000名新生儿中的1名，在幼儿期出现症状，通常在20-30岁时致命。大多数CLN 3 Batten患者具有包含外显子7和8的缺失（CLN 3 Δ ex 7/8），产生阅读移码。在这里，我们证明，这种缺失的小鼠可以有效地治疗使用反义寡核苷酸（阿索），诱导外显子跳跃，以恢复开放的阅读框架。用外显子5靶向的ASO单次治疗新生小鼠一年多，诱导了稳健的外显子跳跃，改善了Cln 3 Δ ex 7/8小鼠的运动协调性，减少了组织病理学，并增加了新的疾病小鼠模型的存活率。ASO还在源自CLN 3 Batten病患者的细胞系中诱导外显子跳跃。我们的研究结果证明了基于ASO的阅读框校正作为治疗CLN 3 Batten病的方法的实用性，并拓宽了使用类似策略治疗其他疾病的ASO的治疗前景。
CLN3 Batten disease is an autosomal recessive, neurodegenerative, lysosomal storage disease caused by mutations in CLN3, which encodes a lysosomal membrane protein. 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 life. Most patients with CLN3 Batten have a deletion encompassing exons 7 and 8 (CLN3Δex7/8), creating a reading frame-shift. 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 Cln3Δex7/8 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.
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影响因子：
46.9
作者：
通讯作者：
--
影响因子：
3.5
作者：
Cotman, SL;Vrbanac, V;MacDonald, ME
通讯作者：
MacDonald, ME
DOI：
10.1007/978-1-61779-767-5_20
发表时间：
2012-01-01
期刊：
EXON SKIPPING: METHODS AND PROTOCOLS
影响因子：
--
作者：
Hua, Yimin;Krainer, Adrian R.
通讯作者：
Krainer, Adrian R.
影响因子：
4.8
作者：
Chandrachud, Uma;Walker, Mathew W.;Cotman, Susan L.
通讯作者：
Cotman, Susan L.
影响因子：
2.5
作者：
D'Andrea, MR;Nagele, RG;Andrade-Gordon, P
通讯作者：
Andrade-Gordon, P