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Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models.
- 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.
- Subjects :
- Amyotrophic Lateral Sclerosis enzymology
Amyotrophic Lateral Sclerosis genetics
Amyotrophic Lateral Sclerosis pathology
Animals
Disease Models, Animal
Humans
Muscle, Skeletal pathology
Oligodeoxyribonucleotides, Antisense genetics
Rats
Rats, Transgenic
Superoxide Dismutase genetics
Superoxide Dismutase-1 genetics
Amyotrophic Lateral Sclerosis drug therapy
Muscle, Skeletal enzymology
Oligodeoxyribonucleotides, Antisense pharmacology
Superoxide Dismutase metabolism
Superoxide Dismutase-1 metabolism
Subjects
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