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.
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.
|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|
|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:|
|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|
|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|
|Reddy, Linga V; Miller, Timothy M (2015) RNA-targeted Therapeutics for ALS. Neurotherapeutics 12:424-7|
|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|
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