Expanding therapeutic opportunities for neurodegenerative diseases: A perspective on the important role of phenotypic screening |
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| Affiliation: | 1. The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami FL 33136, USA;2. Center for Computational Science, University of Miami Miller School of Medicine, Miami FL 33136, USA;3. Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, 1400 NW 12th Ave, Miami, FL 33136, USA;4. Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami FL 33136, USA;1. South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia;2. The College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia;3. Psychiatry, and Neuroscience & Physiology; College of Medicine, SUNY Upstate Medical University, Syracuse, NY, United States;4. Psychiatry, Neuroscience & Physiology, Pharmacology, and Medicine; College of Medicine, SUNY Upstate Medical University, Syracuse, NY, United States;1. Wolfson Centre for Inherited Neuromuscular Disease, RJAH Orthopaedic Hospital, Oswestry SY10 7AG, UK;2. Institute for Science and Technology in Medicine, Keele University, Staffordshire ST5 5BG, UK;3. Centre for Integrative Physiology, University of Edinburgh, UK;4. Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, UK;5. Division of Neurobiology, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, UK |
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| Abstract: | Over the last 20 years, there have been remarkably few FDA-approved first-in-class drugs for neurodegenerative diseases. Debilitating conditions such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis have no effective disease-modifying therapeutics on the market, signifying an area of high unmet medical need where novel approaches are needed. Using a phenotypic screening approach, two separate groups discovered small molecule non-antisense oligonucleotide splice modulators for spinal muscular atrophy, a severe monogenetic disease that causes the degeneration of alpha motor neurons in the spinal cord. These compounds function by a novel mechanism: selective stabilization of the interaction of U1 small nuclear ribonucleic protein (snRNP), a core component of the spliceosome, with the 5′ splice site of a pre-mRNA. The ability of the phenotypic screening approach to uncover a previously unknown mechanism and reveal a new druggable target class has broader implications for other neurodegenerative diseases. |
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| Keywords: | Phenotypic screening Drug discovery Neurodegenerative disease Spinal muscular atrophy SMA |
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