# Fluorescent IRE Sensor for Synucleinopathy Drug Discovery

> **NIH NIH R44** · LUCERNA, INC. · 2022 · $853,817

## Abstract

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.

## Key facts

- **NIH application ID:** 10608833
- **Project number:** 1R44NS130946-01
- **Recipient organization:** LUCERNA, INC.
- **Principal Investigator:** Wen Shen
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $853,817
- **Award type:** 1
- **Project period:** 2022-09-22 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10608833

## Citation

> US National Institutes of Health, RePORTER application 10608833, Fluorescent IRE Sensor for Synucleinopathy Drug Discovery (1R44NS130946-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10608833. Licensed CC0.

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