期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 128, 期 8, 页码 3558-3567出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI99081
关键词
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资金
- NIH, National Institute of Neurological Disorders and Stroke (NINDS) [R01NS078398, U01NS084970]
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [U01NS084970, R01NS078398] Funding Source: NIH RePORTER
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 SOD1(G93A) rats and by almost 40 days in SOD1(G93A) mice. We demonstrated that the initial loss of compound muscle action potential in SOD1(G93A) 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.
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