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)
Project #
Application #
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Gubitz, Amelie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Schools of Medicine
Saint Louis
United States
Zip Code
Bali, Taha; Self, Wade; Liu, Jingxia et al. (2016) Defining SOD1 ALS natural history to guide therapeutic clinical trial design. J Neurol Neurosurg Psychiatry :
Schoch, Kathleen M; DeVos, Sarah L; Miller, Rebecca L et al. (2016) Increased 4R-Tau Induces Pathological Changes in a Human-Tau Mouse Model. Neuron 90:941-7
O'Rourke, J G; Bogdanik, L; Yáñez, A et al. (2016) C9orf72 is required for proper macrophage and microglial function in mice. Science 351:1324-9
Reddy, Linga V; Miller, Timothy M (2015) RNA-targeted Therapeutics for ALS. Neurotherapeutics 12:424-7
Crisp, Matthew J; Mawuenyega, Kwasi G; Patterson, Bruce W et al. (2015) In vivo kinetic approach reveals slow SOD1 turnover in the CNS. J Clin Invest 125:2772-80
Paganoni, Sabrina; Hyman, Theodore; Shui, Amy et al. (2015) Pre-morbid type 2 diabetes mellitus is not a prognostic factor in amyotrophic lateral sclerosis. Muscle Nerve 52:339-43
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
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
DeVos, Sarah L; Goncharoff, Dustin K; Chen, Guo et al. (2013) Antisense reduction of tau in adult mice protects against seizures. J Neurosci 33:12887-97
DeVos, Sarah L; Miller, Timothy M (2013) Antisense oligonucleotides: treating neurodegeneration at the level of RNA. Neurotherapeutics 10:486-97

Showing the most recent 10 out of 14 publications