Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models
Alex McCampbell, … , Eric E. Swayze, Timothy M. Miller
Alex McCampbell, … , Eric E. Swayze, Timothy M. Miller
Published July 16, 2018
Citation Information: J Clin Invest. 2018;128(8):3558-3567. https://doi.org/10.1172/JCI99081.
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Research Article Neuroscience

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

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.

Authors

Alex McCampbell, Tracy Cole, Amy J. Wegener, Giulio S. Tomassy, Amy Setnicka, Brandon J. Farley, Kathleen M. Schoch, Mariah L. Hoye, Mark Shabsovich, Linhong Sun, Yi Luo, Mingdi Zhang, Nicole Comfort, Bin Wang, Jessica Amacker, Sai Thankamony, David W. Salzman, Merit Cudkowicz, Danielle L. Graham, C. Frank Bennett, Holly B. Kordasiewicz, Eric E. Swayze, Timothy M. Miller

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Figure 4

SOD1 ASO injected at 9 weeks of age is able to reverse CMAP amplitudes and lower serum pNFH levels in SOD1G93A mutant mice.

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SOD1 ASO injected at 9 weeks of age is able to reverse CMAP amplitudes a...
(A and B) Mice were injected once at 9 weeks of age with either a control ASO or with ASO 3 (100 μg). (A) CMAP amplitudes at the tibialis anterior muscles were recorded at baseline (5 weeks) and then every other week thereafter (n = 12 per group, average ± SEM). On the week of dosing (9 weeks), CMAP was recorded prior to i.c.v. injection. Typically, SOD1 mice show a steady decline in the CMAP amplitudes recorded at the tibialis anterior; however, one single dose of ASO 3 at 9 weeks of age was able to reverse the trend and by 15 weeks the ASO 3–treated mice had CMAP amplitudes significantly higher than mice treated with a control ASO (P < 0.001, 2-way ANOVA). (B) Blood was collected from each animal at 9, 11, 13, 15, and 17 weeks of age and pNFH levels were quantified. pNFH serum levels of control mice showed a steady increase whereas those of ASO 3–treated mice did not. Levels at 15 weeks: inactive ASO, 19.9 ng/ml ± 5.1 ng/ml; ASO 3, 10.6 ng/ml ± 2.5 ng/ml. Levels at 17 weeks: inactive ASO, 33.96 ng/ml ± 9.3 ng/ml; ASO 3, 16.5 ng/ml ± 4.3 ng/ml. P < 0.0001, 2-way ANOVA, n = 12 per group, average ± SEM.