Fluorescent IRE sensor for synucleinopathy drug discovery
Ended Project Grant Awarded Last action
- Award ID
- R44NS130946
- Recipient
-
Lucerna Inc. UEI J3MWGA6WFCG3
- Awarding agency
-
National Institute of Neurological Disorders and Stroke
National Institutes of Health, Department of Health and Human Services
- Obligated
- $5,184,693
Award facts
- Assistance listing
- 93.866 Aging Research
- Completion date
- Originally
- Funding agency
- National Institute on Aging National Institutes of Health, Department of Health and Human Services
- Place of performance
- New York, USA
Award details come from USAspending.gov.
Description
- Abstract
- 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.
Transactions
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| Amendment | $0 | |
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| Amendment | $874,414 | |
| Amendment | $874,414 | |
| Amendment | $874,414 | |
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| Amendment | $853,817 | |
| Amendment | $853,817 | |
| Original award | $853,817 |
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Quick answers
Who received award R44NS130946?
R44NS130946 was awarded to Lucerna Inc. by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on September 22, 2022.
How much is award R44NS130946 worth?
$5,184,693 has been obligated on R44NS130946.
Which agency awarded R44NS130946?
National Institute of Neurological Disorders and Stroke (National Institutes of Health) awarded R44NS130946, with funding from National Institute on Aging (National Institutes of Health).
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