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Targeting endothelial arginase to treat diabetes-associated vascular dysfunction

Award Information

Agency:
Department of Health and Human Services
Branch:
N/A
Award ID:
Program Year/Program:
2010 / STTR
Agency Tracking Number:
R41HL095232
Solicitation Year:
2010
Solicitation Topic Code:
NHLBI
Solicitation Number:
PA09-081
Small Business Information
ARGINETIX, INC.
Corridor Pharmaceuticals, Inc. 2330 W JOPPA RD, STE 330 LUTHERVILLE, MD 21093-4690
View profile »
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No
 
Phase 1
Fiscal Year: 2010
Title: Targeting endothelial arginase to treat diabetes-associated vascular dysfunction
Agency: HHS
Contract: 1R41HL095232-01A2
Award Amount: $365,333.00
 

Abstract:

DESCRIPTION (provided by applicant): The product that will result from this STTR is ABH (2(S)-amino-6-boronohexanoic acid), a potent small molecule inhibitor of the enzyme arginase, for treating vascular complications of diabetes. There are 20.8 million Americans with diabetes. More than 65% of these people will die from heart disease or stroke. Men with diabetes are twice as likely, and women with diabetes are three times as likely, to have cardiovascular disease compared to non-diabetic counterparts of equivalent age. Other vascular complications of diabetes include retinopathy, neuropathy, peripheral ischemia, and erectile dysfunction (ED). Recently it has been found that endothelial arginase is elevated in vascular disorders associated diabetes, as wellas with old age, and atherosclerosis. It is thought that the mechanism by which arginase leads to vascular dysfunction is by competing with nitric oxide synthase (NOS) for its essential substrate, L-arginine. This limits the production of NO, a critical signaling molecule responsible for maintaining vascular health, and leads to uncoupling of NOS and the production of damaging reactive oxygen species (ROS). This mechanism provides a powerful rationale for the use of arginase inhibitors, such as ABH, as a treatment to reverse the damaging consequences of vascular elevations in this enzyme. ABH has proven to be the most potent inhibitor of both arginase isoforms in all species tested. Preliminary data indicate that ABH effectively augments vascular smooth muscle relaxation ex vivo, inhibiting arginase activity in vascular tissues collected from diabetic animals and humans, while in vivo ABH treatment improves parameters of vascular endothelial function. Furthermore the pharmacokinetic and toxicology profile support this small molecule as an excellent lead compound. ABH is the only arginase inhibitor that is reported to be effective in altering measures of vascular endothelial function in vivo. In the current proposal, Arginetix will use a validated animal modelof Type 2 diabetes (the Zucker Diabetic Fatty rat) to characterize the effectiveness of ABH in improving measures of vascular endothelial function ex vivo, and in vivo. In Phase 2, ABH will be further developed either as a standalone or combination treatment for diabetes-associated ED. Sufficient toxicology, pharmacology, and manufacturing data will be collected to enable an IND to be filed with the FDA. PUBLIC HEALTH RELEVANCE: This STTR project will contribute to human health by providing a new treatment for complications that affect the blood vessels of people with diabetes. These complications, which can result in cardiovascular disease, blindness, gangrene, kidney disease, and erectile dysfunction, are still major causes of death and disease among people with diabetes. This project will produce the first data demonstrating the effectiveness of a new drug to treat diseases associated with these blood vessel complications of diabetes.

Principal Investigator:

Dan E. Berkowitz
410-955-7519
dberkow1@jhmi.edu

Business Contact:

Simon Aspland
443-279-9971
saspland@arginetix.com
Small Business Information at Submission:

ARGINETIX, INC.
Corridor Pharmaceuticals, Inc. 2330 W JOPPA RD, STE 330 LUTHERVILLE, MD 21093-4690

EIN/Tax ID: 126224748
DUNS: N/A
Number of Employees: N/A
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No
Research Institution Information:
Johns Hopkins University
Som Office Of Research Admin
Broadway Research Bldg Suite 117
BALTIMORE, MD 21205-
Contact: