The goal of this Phase II proposal is to advance synucleinopathy disease drug discovery by validating a high- throughput screening (HTS)-ready assay and establish a RNA structure sensor platform for RNA-targeted drug discovery. Dementia with Lewy bodies is the second most common form of degenerative dementia in the elderly population after Alzheimer's disease; and it is characterized by abnormal accumulation of alpha-synuclein (SNCA) aggregates. Diseases featuring pathogenic SNCA proteins are collectively known as synucleinopathies, which also include Parkinson's disease, multiple system atrophy, and Alzheimer's Disease with Amygdala restricted Lewy bodies. There is currently no disease-modifying cure available for any of the synucleinopathies. It is known that SNCA gene duplication increases SNCA levels and is correlated with disease progression and severity, leading to early parkinsonism and dementia. Studies showed reductions in SNCA levels can reduce aggregation, prevent Lewy body formation, and confer neuroprotection. Thus, inhibiting SNCA expression during disease prodromal phase has the potential to slow disease progression or halt disease onset. SNCA translation is controlled by an iron-response element (IRE) in the 5'UTR of the mRNA. To demonstrate feasibility, we developed proof-of-concept RNA structure sensors that were responsive to the binding of small molecules and antisense oligonucleotides, and demonstrated feasibility for HTS use. To accomplish the goal of this proposal, we will complete the following specific aims: 1) Finalize HTS optimization of the SNCA-specific RNA sensor and perform a pilot screen, 2) Establish the generalizability of the RNA structure sensor platform by developing HTS- compatible sensors targeting another pathogenic RNA structure, 3) Develop a standard operating procedure for the commercialization of custom RNA sensor services, 4) Perform a primary screen to identify inhibitors of SNCA protein translation. If successful, we will have a validated HTS assay for synucleinopathy drug discovery and a RNA structure sensor platform that aimed to accelerate the current pace in RNA structure-based drug discovery and to enable more RNA-targeted drug development programs targeting disease-causing RNA structures.
Public Health Relevance Statement: PROJECT NARRATIVE Synucleinopathies are a group of neurodegenerative diseases characterized by the progressive accumulation of alpha-synuclein protein aggregates in neurons and glial cells. There is currently no disease-modifying therapy available for synucleinopathies, which include Parkinson's disease, dementia with Lewy body, multiple system atrophy, and Alzheimer's Disease with Amygdala restricted Lewy bodies. This project will develop a high- throughput screening platform targeting a new synucleinopathy disease mechanism, identify potential hits ready for lead optimization, and develop a generalizability RNA structure sensor platform to enable more RNA-targeted drug discovery programs targeting disease-causing RNA structures.
Project Terms: success; chemical library; small molecule libraries; neuroprotection; 5'UTR; mRNA Leader Sequences; 5' Untranslated Regions; Response Elements; Structure; assay development; High Throughput Assay; high throughput screening; drug discovery; Pathogenicity; Molecular Interaction; Binding; preventing; prevent; small molecule; SNCA gene; Symptoms; Affinity; Data; Diversity Library; Reproducibility; Validation; Pathologic; Development; developmental; protein aggregation; insoluble aggregate; protein aggregate; Population; synucleinopathy; stem; commercialization; experimental study; experiment; experimental research; lead optimization; Lewy body pathology; LB pathology; Lewy pathology; Dementia with Lewy Bodies; National Center for Advancing Translational Sciences; NCATS; RNA-targeting therapy; RNA targeting drug; RNA targeting therapeutics; Age; ages; Elderly; advanced age; elders; geriatric; late life; later life; older adult; older person; senior citizen; Alzheimer's Disease; AD dementia; Alzheimer; Alzheimer Type Dementia; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's disease dementia; Alzheimers Dementia; Alzheimers disease; Primary Senile Degenerative Dementia; dementia of the Alzheimer type; primary degenerative dementia; senile dementia of the Alzheimer type; Amygdaloid structure; Amygdala; Amygdaloid Body; Amygdaloid Nucleus; amygdaloid nuclear complex; inhibitor; Biological Assay; Assay; Bioassay; Biologic Assays; Buffers; Cells; Cell Body; Disease; Disorder; Elements; Future; Gene Duplication; Goals; In Vitro; Libraries; Luciferases; Luciferase Immunologic; Glia; Glial Cells; Kolliker's reticulum; Neuroglial Cells; Non-neuronal cell; Nonneuronal cell; nerve cement; Neuroglia; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; neuronal; Neurons; Paralysis Agitans; Parkinson; Parkinson's disease; Parkinsons disease; Primary Parkinsonism; Parkinson Disease; Production; Program Development; Reagent; Non-Polyadenylated RNA; RNA Gene Products; Ribonucleic Acid; RNA; mRNA; Messenger RNA; Robotics; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Signal Transduction; Specificity; Standardization; Testing; Time; Translations; Antisense Oligonucleotides; Anti-Sense Oligonucleotides; Antisense Agent; anti-sense agent; anti-sense oligo; antisense oligo; Amyloid beta-Protein Precursor; Amyloid A4 Protein Precursor; Amyloid Protein Precursor; Amyloid ß-Protein Precursor; amyloid precursor protein; Lewy Bodies; Custom; Guidelines; base; dosage; sensor; improved; Procedures; Phase; Biological; biologic; Ensure; Chemicals; Parkinsonian; Parkinsonian Condition; Parkinsonian Diseases; Parkinsonian Syndrome; Parkinsonism; Parkinsonian Disorders; Measurement; Disease Progression; Fees for Service; Fee-for-Service Plans; disease onset; disorder onset; Onset of illness; NAC precursor; PARK1 protein; PARK4 protein; SNCA; SNCA protein; a-syn; a-synuclein; alphaSP22; asyn; non A-beta component of AD amyloid; non A4 component of amyloid precursor; a-syn; a-synuclein; alpha synuclein; Therapeutic; Fe element; Iron; Life; programs; Dysautonomia-Orthostatic Hypotension Syndrome; Dysautonomic Orthostatic Hypotension; Multiple System Atrophy Syndrome; Multisystem Atrophy; Multisystemic Atrophy; Progressive Autonomic Failure; Shy-Drager Syndrome; Shy-Drager Type Idiopathic Orthostatic Hypotension; Multiple System Atrophy; Protocol; Protocols documentation; Source; Amentia; Dementia; disease severity; Severity of illness; Degenerative Neurologic Diseases; Degenerative Neurologic Disorders; Nervous System Degenerative Diseases; Neural Degenerative Diseases; Neural degenerative Disorders; Neurodegenerative Diseases; Neurologic Degenerative Conditions; degenerative diseases of motor and sensory neurons; degenerative neurological diseases; neurodegenerative illness; Neurodegenerative Disorders; Services; Performance
