# Drug Discovery Pipeline Targeting Pathologically Leaky Calcium Release Channels in Age-Related Indications

> **NIH NIH R43** · PHOTONIC PHARMA, LLC · 2021 · $499,443

## Abstract

Project Summary
Photonic Pharma LLC (PP) proposes a Phase I SBIR project to launch high-throughput screening (HTS) for
discovery of small-molecule allosteric inhibitors of pathologically leaky ryanodine receptor (RyR) calcium (Ca)
release channels, to arrest or reverse age-related neurodegeneration, focused on Alzheimer’s disease
(AD). In AD, dysregulated intracellular Ca fuels a pathophysiological vicious cycle. RyRs are responsible for
triggered Ca release from intracellular storage organelles (sarcoplasmic reticulum – SR; endoplasmic reticulum
– ER). The resulting Ca signaling is essential for many cellular processes in muscle and non-muscle cells.
Dysregulated RyR function, producing a Ca-leaky state of the resting ER/SR, has been identified as a key
contributor to age-related pathologies, particularly AD. In this proposal, we target RyR2, the predominant brain
isoform, which has been clearly identified as a target for AD pathogenesis and therapy. We have
translated our academic research at UMN toward fluorescence-based HTS structural assays targeting RyR2
(US patent 10,281,476). This FRET assay uses fluorescently labeled RyR2 modulators, calmodulin (CaM) and
FKBP12.6 (FKBP), to monitor RyR2-CaM binding. Using small pilot screens, we have demonstrated an
inverse correlation between compound effects on our FRET readout and resting RyR2 activity (Ca leak). This
established an HTS platform to identify allosteric regulators with therapeutic potential to alleviate RyR2 Ca
leak. In our academic work at UMN, we have a funded R01 grant to apply this technology to studying RyR2
function and therapy in the heart; PP has obtained an exclusive commercial license for this UMN patent. In this
project, we will apply this technology for therapeutic discovery to correct intracellular Ca signaling in
Alzheimer’s disease. In Phase I, we will establish a screening funnel for (a) a large-scale HTS campaign
and (b) subsequent lead development via structure-activity relationship (SAR) studies. In Phase II, we will
expand SAR, and begin cell-based and animal studies using models of AD. To achieve the objectives in Phase
I, PP (1) has demonstrated experience applying this FRET system for RyR2-targeted HTS, (2) will use its
proprietary high-precision, high-throughput FLT plate reader (FLT-PR), (3) has functionally validated Hits
yielded by this HTS platform, and (4) has identified leak inhibitors of RyR2 in heart. The Phase I Specific Aims:
Aim 1 – Primary HTS of a 50,000-compound CNS-selected library, to identify compounds that correct the
leaky RyR state. Aim 2 – Determine functional effects of Hits from Aim 1. We have assembled an
outstanding interdisciplinary team, including academic experts from several universities (medicinal chemist
Aldrich at UMN; RyR2 AD expert Stutzmann at Rosalind Franklin University, human RyR2 expert Zima at
Loyola University Chicago, complementing the Photonic team’s expertise on AD-targeted HTS. These
collaborations, and our track recor...

## Key facts

- **NIH application ID:** 10157143
- **Project number:** 1R43AG069582-01A1
- **Recipient organization:** PHOTONIC PHARMA, LLC
- **Principal Investigator:** RAZVAN LIVIU CORNEA
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $499,443
- **Award type:** 1
- **Project period:** 2021-01-15 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10157143

## Citation

> US National Institutes of Health, RePORTER application 10157143, Drug Discovery Pipeline Targeting Pathologically Leaky Calcium Release Channels in Age-Related Indications (1R43AG069582-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10157143. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*