exon skipping

https://doi.org/10.1038/s41591-020-0986-1

https://pubmed.ncbi.nlm.nih.gov/32719489/

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

ALTERNATIVE TITLE:
None

DATE:
Tue, 28 Jul 2020 06:00:00 -0400

AUTHORS:
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

SOURCE:
Nature medicine

DESCRIPTION:
CLN3 Batten disease is an autosomal recessive, neurodegenerative, lysosomal storage disease caused by mutations in CLN3, which encodes a lysosomal membrane protein^(1-3). 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 life^(4-7). Most patients with CLN3 Batten have a deletion encompassing exons 7 and 8 (CLN3^(∆ex7/8)), creating a reading frameshift^(7,8). Here…

CONTENT:
Nat Med. 2020 Jul 27. doi: 10.1038/s41591-020-0986-1. Online ahead of print.

ABSTRACT

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.

PMID:32719489 | DOI:10.1038/s41591-020-0986-1

PUBMED ID:
pubmed:32719489

OTHER ID:
pmid:32719489,doi:10.1038/s41591-020-0986-1

PUBLICATION DATE:
Tue, 28 Jul 2020 06:00:00 -0400
2020-07-29

RETRIEVAL DATE :
07/28/20 06:27AM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/32719489/?utm_source=MS-Office&utm_medium=rss&utm_campaign=pubmed-2&utm_content=1nWYA0Nnwr_wLHWsIDX2btUvlzF91Kc2m_rAz6Uc2Ke1bh4s-l&fc=20200622115739&ff=20200728062723&v=2.11.4

LINK – DOI:
https://doi.org/10.1038/s41591-020-0986-1

LINK – FULL TEXT:
Pending

NOTES:
None