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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Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Gubitz, Amelie
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Washington University
Schools of Medicine
Saint Louis
United States
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Hoye, Mariah L; Archambault, Angela S; Gordon, Taylor M et al. (2018) MicroRNA signature of central nervous system-infiltrating dendritic cells in an animal model of multiple sclerosis. Immunology 155:112-122
Sato, Chihiro; Barthélemy, Nicolas R; Mawuenyega, Kwasi G et al. (2018) Tau Kinetics in Neurons and the Human Central Nervous System. Neuron 98:861-864
McCampbell, Alex; Cole, Tracy; Wegener, Amy J et al. (2018) Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models. J Clin Invest 128:3558-3567
Sato, Chihiro; Barthélemy, Nicolas R; Mawuenyega, Kwasi G et al. (2018) Tau Kinetics in Neurons and the Human Central Nervous System. Neuron 97:1284-1298.e7
DeVos, Sarah L; Miller, Rebecca L; Schoch, Kathleen M et al. (2017) Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci Transl Med 9:
Hoye, Mariah L; Koval, Erica D; Wegener, Amy J et al. (2017) MicroRNA Profiling Reveals Marker of Motor Neuron Disease in ALS Models. J Neurosci 37:5574-5586
Bali, Taha; Self, Wade; Liu, Jingxia et al. (2017) Defining SOD1 ALS natural history to guide therapeutic clinical trial design. J Neurol Neurosurg Psychiatry 88:99-105
Gendron, Tania F; Chew, Jeannie; Stankowski, Jeannette N et al. (2017) Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis. Sci Transl Med 9:
Gendron, Tania F; C9ORF72 Neurofilament Study Group; Daughrity, Lillian M et al. (2017) Phosphorylated neurofilament heavy chain: A biomarker of survival for C9ORF72-associated amyotrophic lateral sclerosis. Ann Neurol 82:139-146
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

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