Accelerating wound repair in diabetes

Project title: A Strategy to Accelerate Diabetic Wound Repair
Institution: University of Notre Dame
Pathway Project Publications: 4
Has delivered 6 presentations related to her Pathway project

Major accomplishments:

We identified active MMP-8 and MMP-9 in wounds of diabetic mice using a novel affinity resin coupled with proteomics. We determined that MMP-9 is detrimental to wound healing, while MMP-8 is involved in the normal healing process of the wound. The best strategy to resolve diabetic chronic wounds is to inhibit the detrimental MMP-9, while sparing the beneficial MMP-8. We have discovered ND-336, a novel potent and selective inhibitor of MMP-9, with a selectivity of 450-fold that accelerates wound healing in diabetic mice. Our compound has better efficacy in diabetic mice than becaplermin, the only FDA-approved drug for treatment of diabetic foot ulcers. We analyzed wound samples from patients with diabetes who have chronic and acute wounds with our affinity resin coupled with proteomics. We identified active MMP-8 and MMP-9 in wounds from people with diabetes, the very same proteinases found in diabetic mouse wounds.

Preliminary results indicate that people with diabetes who have chronic wounds exhibit higher levels of active MMP-9 in than those with acute wounds. These data suggest that the mechanisms of pathology and repair are similar in humans and mice. MMP-9 is a novel target for treatment of diabetic foot ulcers. ND-336 shows promise in moving forward for intervention in this intractable complication of diabetes.

Impact statement:

Diabetes affects 340 million people in the world and 29.1 million individuals in the United States. Approximately one in four people with diabetes develop diabetic foot ulcers in their lifetime, resulting in 900,000 diabetic foot ulcers every year in the United States. The standard of care for diabetic foot ulcers are debridement, off-loading, and infection control. There is a single FDA-approved drug (becaplermin) for treatment of diabetic foot ulcers, however efficacy is modest and it carries increased risk of cancer and mortality. The current limited therapies are not effective, resulting in 73,000 amputations every year in the United States.

With funding from the Pathway award, I have discovered a novel target for pharmaceutical intervention in the treatment of diabetic foot ulcers. Our compound shows better efficacy in diabetic mice than becaplermin. The Pathway award has allowed me to contribute to the understanding of diabetic foot ulcers and to discover a pharmacological recourse for the betterment of people with diabetes.

I am invested in understanding this disease for personal reasons, as diabetes has impacted my family. However, I am also cognizant of the profound impact that this disease has on the global human population. I am very excited about bringing forward a new therapeutic agent for the treatment of diabetic foot ulcers.