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

被引:0
作者
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
机构
[1] Rosalind Franklin University of Medicine and Science,Center for Genetic Diseases, Chicago Medical School
[2] Rosalind Franklin University of Medicine and Science,School of Graduate and Postdoctoral Studies
[3] Sanford Research,Pediatrics and Rare Diseases Group
[4] Ionis Pharmaceuticals,Cellular and Molecular Pharmacology, Chicago Medical School
[5] Rosalind Franklin University of Medicine and Science,Department of Pediatrics, Sanford School of Medicine
[6] University of South Dakota,undefined
来源
Nature Medicine | 2020年 / 26卷
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摘要
CLN3 Batten disease is an autosomal recessive, neurodegenerative, lysosomal storage disease caused by mutations in CLN3, which encodes a lysosomal membrane protein1–3. 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 life4–7. Most patients with CLN3 Batten have a deletion encompassing exons 7 and 8 (CLN3∆ex7/8), 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 Cln3∆ex7/8 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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页码:1444 / 1451
页数:7
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