Targeting Mmp-9 For Treatment Of Diabetic Foot Ulcers
Trung T. Nguyen, Zhihong Peng, William R. Wolter, Jeffrey I. Jones, Charles E. Peterson, Shahriar Mobashery, Mayland Chang.
University of Notre Dame, Notre Dame, IN, USA.
The molecular basis for why diabetic foot ulcers (DFUs) are recalcitrant to healing has not been fully understood. A single drug, becaplermin, approved by the FDA for this ailment 20 years ago, is not standard of care. We elucidated that MMP-9 is the biochemical culprit in this recalcitrance and discovered a selective MMP-9 inhibitor referred to as (R)-ND-336, which speeds up healing in diabetic mice better than becaplermin. Treatment with becaplermin resulted in reduced MMP-9 activity. On the other hand, aclerastide, a peptide analog of angiotensin II that failed in phase 3 clinical trials for the treatment of DFUs, increased MMP-9 activity and is likely a contributor to its clinical failure. We validated the target MMP-9 in humans and found that the more severe and infected DFUs have 34-fold higher levels of MMP-9 than non-diabetic controls. The purpose of this study was to evaluate the efficacy of (R)-ND-336 in infected diabetic mice. Diabetic mice were inflicted with full-thickness wounds and infected with Staphylococcus epidermidis biofilm; delayed wound healing, increased inflammation, and upregulation of active MMP-9 in macrophages were observed compared to uninfected wounds. Upregulation of MMP-9 in infected diabetic mice paralleled the higher levels of active MMP-9 observed in the more severe and infected human DFUs. Topical treatment of infected diabetic mouse wounds with (R)-ND-336 was started on day 7 and was found to accelerate wound healing. (R)-ND-336 holds promise as a therapeutic agent for the treatment of DFUs.
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