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Drug regulators of nitric oxide production as Alzheimer's disease therapeutics

Award Information

Agency:
Department of Health and Human Services
Branch:
N/A
Award ID:
Program Year/Program:
2012 / STTR
Agency Tracking Number:
R41AG043243
Solicitation Year:
2012
Solicitation Topic Code:
NIA
Solicitation Number:
PAR09-259
Small Business Information
EPIGEN BIOSCIENCES, INC.
10225 Barnes Canyon Road suite A104 SAN DIEGO, CA -
View profile »
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No
 
Phase 1
Fiscal Year: 2012
Title: Drug regulators of nitric oxide production as Alzheimer's disease therapeutics
Agency: HHS
Contract: 1R41AG043243-01
Award Amount: $726,746.00
 

Abstract:

DESCRIPTION (provided by applicant): Druggable regulators of nitric oxide production as new Alzheimer's disease therapeutics Summary: Nitrosative stress is a critical mediator of the onset and progression of Alzheimer's disease (AD): it precedes and is associated with neuritic dystrophy and dendritic spine loss, A /amyloid accumulation and deposition, cholinergic denervation and a memory loss phenotype in animal models of disease. Normally, nitric oxide (NO) is an important signaling molecule and the enzymethat produces it, nitric oxide synthase (NOS), regulates ApoE and its other protein partners via nitrosylation. Under pro-inflammatory conditions (e.g. AD), oxidative stress upregulates NOS. Excess NO combines with oxygen radicals forming the reactive nitrosylating species peroxynitrite, which in turn causes promiscuous dysregulation and indiscriminate damage. Because direct inhibition of NOS results in systemic toxicity, our unique strategy is to selectively reduce NO activity at sites of inflammation. This will be achieved by targeting Sigma- 1 receptors (S1R), because they become important regulators of NOS activity only under conditions of oxidative stress. Our hypothesis is that elevated brain NO levels can be lowered at inflammatory sites by drugs that promote S1R-mediated reductions in NOS activity. The path for discovery and proof-of-concept phases includes: A) synthesis of additional novel candidate molecules to impart the appropriate selectivity and drug-like characteristics to compounds that reduce NO levels and promote neuronal and/or glial cell survival in vitro under conditions of nitrosative stress; B) evaluate 1- of these leads in a transgenic mouse model of AD by measuring reductions in CNS A /amyloid burden, 3-nitrotyrosine levels and improvements in cognition. Novel high affinity S1R candidates (hits) have been identified in our preliminary work and now we seek to create leads with refined drug-like properties for testing our target and mechanism- based hypothesis for therapeutics designed to slow the progression of AD. PUBLIC HEALTH RELEVANCE: The objective is to discover and develop news drugs for the treatment of Alzheimer's disease, a leading cause of morbidity and mortality in the US.

Principal Investigator:

John A. Schetz
817-735-2064
jschetz@hsc.unt.edu

Business Contact:

Fabio C. Tucci
619-917-0639
ftepigen@gmail.com
Small Business Information at Submission:

EPIGEN BIOSCIENCES, INC.
10225 Barnes Canyon Road suite A104 SAN DIEGO, CA -

EIN/Tax ID: 127289310
DUNS: N/A
Number of Employees: N/A
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No
Research Institution Information:
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
UNIVERSITY OF TEXAS HLTH SCI CTR
BOX 20036
HOUSTON, TX 77225-
Contact: