Discovery and development of OGG1 activators as precision drugs for modification of alzheimer's disease progression
Ended Project Grant Awarded Last action
- Award ID
- R43AG084412
- Recipient
-
Luciole Pharmaceuticals, Inc. UEI E26HJPMM1E86
- Awarding agency
-
National Institute on Aging
National Institutes of Health, Department of Health and Human Services
- Obligated
- $501,626
Award facts
- Assistance listing
- 93.866 Aging Research
- Completion date
- Originally
- Place of performance
- Massachusetts, USA
Award details come from USAspending.gov.
Description
- Abstract
- Alzheimer's disease (ad) is a leading cause of dementia with 1 in 85 adults affected worldwide. The lack of disease-modifying therapies or mechanistic biomarkers to reliably monitor treatment are key unmet needs. Current standard of care (SOC), i.e., acetylcholinesterase or nmda receptor blockade, provides limited symptom-relief. Current evidence indicates that an inter-related, mechanistic triad is formed in ad by oxidative stress (OXS), mitochondrial (MT) dysfunction and inflammation. This pathological trio occurs early and is fundamental to ad. OXS primarily arises from unproductive MT-respiration and promotes MT-dysfunction. Oxidized guanine (8-OXO-DG) is the most prominent oxidative and mutagenic DNA lesion, particularly in mtdna. Excessive amounts signify insufficient repair. Improving MT-function by enhancing mtdna repair will modify ad progression. Repair of 8-OXO-DG is an indispensable, mitochondrial quality control mechanism that largely occurs by base excision repair. Accumulation of 8-OXO-DG leads to double-stranded breaks which cause mtdna deletions and fragmentation and culminates in loss of bioenergetic capacity and cell viability, a prominent ad pathological feature. Fragmented mtdna is expulsed to stimulate multiple proinflammatory pathways. Although there are MT-approaches with potential for ad treatment, there are presently no therapies that target base excision repair of oxidative damage. Luciole pharmaceuticals' approach is to improve DNA repair using small molecules to enhance the catalytic activity of the DNA glycosylase, OGG1. In the first step of base excision repair, OGG1 excises 8-OXO-DG while recruiting other pathway enzymes to complete repair in the nucleus and mitochondria. Increasing OGG1 activity will result in the efficient removal of 8-OXO-DG to prevent strand breaks. Ultimately, energetics and inflammation will improve to preserve neuronal function and slow ad progression. Recent publications using either physio- or pharmacological approaches in ad murine models support our hypothesis. Building on our previous success in discovering novel OGG1 activators (oaas), we will develop "first-in-class" orally available, small molecule oaas that are differentiated from ad SOC drugs to modify ad and advance patient quality of life in a multi-billion-dollar market. In this phase i sbir project, we plan to progress OAA chemistry and in vitro screening assays to improve OAA potency and in vivo efficacy. If successful, our phase II project will include; 1) advancing a lead to candidate selection, 2) testing optimized compounds for mtdna expulsion in challenged human-derived ipscs and murine ad models, 3) early safety assessment and 4) generating a novel mutant mouse model for testing the candidate compound.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $0 | |
| Amendment | $198,117 | |
| Amendment | $0 | |
| Original award | $303,509 |
Quick answers
Who received award R43AG084412?
R43AG084412 was awarded to Luciole Pharmaceuticals, Inc. by National Institute on Aging (National Institutes of Health) on September 18, 2023.
How much is award R43AG084412 worth?
$501,626 has been obligated on R43AG084412.
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