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Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models.

Authors :
McCampbell A
Cole T
Wegener AJ
Tomassy GS
Setnicka A
Farley BJ
Schoch KM
Hoye ML
Shabsovich M
Sun L
Luo Y
Zhang M
Comfort N
Wang B
Amacker J
Thankamony S
Salzman DW
Cudkowicz M
Graham DL
Bennett CF
Kordasiewicz HB
Swayze EE
Miller TM
Source :
The Journal of clinical investigation [J Clin Invest] 2018 Aug 01; Vol. 128 (8), pp. 3558-3567. Date of Electronic Publication: 2018 Jul 16.
Publication Year :
2018

Abstract

Mutations in superoxide dismutase 1 (SOD1) are responsible for 20% of familial ALS. Given the gain of toxic function in this dominantly inherited disease, lowering SOD1 mRNA and protein is predicted to provide therapeutic benefit. An early generation antisense oligonucleotide (ASO) targeting SOD1 was identified and tested in a phase I human clinical trial, based on modest protection in animal models of SOD1 ALS. Although the clinical trial provided encouraging safety data, the drug was not advanced because there was progress in designing other, more potent ASOs for CNS application. We have developed next-generation SOD1 ASOs that more potently reduce SOD1 mRNA and protein and extend survival by more than 50 days in SOD1G93A rats and by almost 40 days in SOD1G93A mice. We demonstrated that the initial loss of compound muscle action potential in SOD1G93A mice is reversed after a single dose of SOD1 ASO. Furthermore, increases in serum phospho-neurofilament heavy chain levels, a promising biomarker for ALS, are stopped by SOD1 ASO therapy. These results define a highly potent, new SOD1 ASO ready for human clinical trial and suggest that at least some components of muscle response can be reversed by therapy.

Details

Language :
English
ISSN :
1558-8238
Volume :
128
Issue :
8
Database :
MEDLINE
Journal :
The Journal of clinical investigation
Publication Type :
Academic Journal
Accession number :
30010620
Full Text :
https://doi.org/10.1172/JCI99081