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 2

SOD1 ASOs prolong onset, survival, and motor performance of SOD1G93A mutant animals.

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SOD1 ASOs prolong onset, survival, and motor performance of SOD1G93A mut...
(A–C) Mice were dosed i.c.v. twice, at day 50 and again at day 94, each time with 300 μg ASO 1 (n = 20 per treatment group, all females). (A) Onset of disease was scored as percentage of animals losing 10% of peak body weight. Median onset for mice treated with the control ASO was 140 days, whereas treatment with ASO 1 increased median onset to 183 days (P < 0.0001, log-rank Mantel-Cox). (B) Motor performance was tested through the rotarod test: mice were tested once a week starting at 80 days of age until they could not stay on the rod for at least 30 seconds. ASO 1 treatment significantly increased rotarod performance: in the control group, the median age at which 50% decrease in performance was reached was 147 days, whereas in the ASO 1–treated animals, the median increased significantly to 182 days (P < 0.0001, 2-way ANOVA). (C) The median survival of mice treated with the control ASO was 168 days, whereas the treatment with ASO 1 increased median survival to 205 days (P < 0.0001, log-rank Mantel-Cox). (D and E) Rats were injected intrathecally with a 1,000 μg single bolus dose of inactive control ASO (n = 16), aCSF vehicle control (n = 19), ASO 333611 (n = 17), ASO 1 (n = 19), or ASO 2 (n = 18). (D) Rats treated with ASO 1 or ASO 2 maintained weight 70 days (P < 0.0001) and 67 days (P < 0.001) longer, respectively, than rats treated with aCSF. 333611 delayed onset of weight loss modestly (median 139 days, compared with aCSF median 121 days). (E) Survival was markedly prolonged in the ASO 1 and ASO 2 treatment groups by 53 days (P < 0.0001) and 64 days (P < 0.0001), respectively, compared with aCSF control treatment in which rats survived to a median age of 166 days. This represents a 32% (ASO 1) and 39% (ASO 2) extension of survival. P values were determined by log-rank (Mantel-Cox) test.