Amyotrophic lateral sclerosis is characterized by the progressive loss of motor neurons in the spinal cord, resulting in stiffness, severe weakness, atrophy of skeletal muscles, and eventual death from respiratory failure in 3-5 years. There are no current therapies that substantially slow the progression of the disease. In animal models and in samples from ALS patients, we have discovered changes in small non-coding RNA called microRNAs. We will now validate one particular microRNA as a therapeutic target and develop a method of inhibiting this microRNA using antisense oligonucleotides. We hypothesize that inhibition of this miRNA will substantially slow ALS in animal models. Given our current experience in Phase I trial using antisense oligonucleotides in ALS patients;we intend to translate our findings from this grant to a novel therapeutic for ALS.

Public Health Relevance

There are no medications that substantially slow the course of ALS. The results of this application have the potential to validate a novel therapeutic target as well as a method of modulating that target. The microRNA target that we have validated is likely also important for other neurodegenerative diseases besides ALS and thus the miRNA inhibitor we are developing may be widely applicable. In addition, we are pioneering the use of antisense oligonucleotide inhibitors of miRNA in the brain and spinal cord, a technology that may have therapeutic implications for many neurological disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Gubitz, Amelie
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Washington University
Schools of Medicine
Saint Louis
United States
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Cady, Janet; Koval, Erica D; Benitez, Bruno A et al. (2014) TREM2 variant p.R47H as a risk factor for sporadic amyotrophic lateral sclerosis. JAMA Neurol 71:449-53
Sanders, David W; Kaufman, Sarah K; DeVos, Sarah L et al. (2014) Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82:1271-88
Miller, Timothy M; Pestronk, Alan; David, William et al. (2013) An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol 12:435-42
DeVos, Sarah L; Miller, Timothy M (2013) Antisense oligonucleotides: treating neurodegeneration at the level of RNA. Neurotherapeutics 10:486-97
Koval, Erica D; Shaner, Carey; Zhang, Peter et al. (2013) Method for widespread microRNA-155 inhibition prolongs survival in ALS-model mice. Hum Mol Genet 22:4127-35
DeVos, Sarah L; Miller, Timothy M (2013) Direct intraventricular delivery of drugs to the rodent central nervous system. J Vis Exp :e50326