Pressure ulcers, also known as bed sores, are chronic wounds that have no medicinal therapies that can heal them; at best, patients who suffer are moved into different positions to prevent the lesions from worsening.
In an article in American Chemical Society’s (ACS) Chemical Biology journal, Mayland Chang, research professor in the Department of Chemistry & Biochemistry, and contributors demonstrated that an experimental drug created at the University of Notre Dame for diabetic foot ulcers, (R)-ND-336, also improved pressure ulcers.
Though they are two different conditions, both resist healing when progress stalls at the inflammation stage. Chang, Shahriar Mobashery, Navari Family Professor in Life Sciences in the Department of Chemistry & Biochemistry, and collaborators discovered that drugs must target the primary reason the wounds don’t heal: certain enzymes called matrix metalloproteinases (MMMPs) stall the process.
“For any wound to heal, the wound needs to go through an orchestrated set of events, in a cycle, where inflammation is resolved, new blood vessels are formed and there is a restructuring of the extracellular matrix (the network of proteins that give cells their structure),” Chang said. “MMPs are involved in all cycles of inflammation, blood-vessel formation and remodeling.”
However, there are 24 MMPs that might be responsible, and all 24 exist in three forms, with only one form capable of preventing the wound from healing and another form capable of repairing the wound. The difficulty, Mobashery said, was to narrow down which of the MMPs should be targeted without affecting this repair function. MMP-8 and MMP-9, the ones the research team discovered affect healing of diabetic foot ulcers, are the same ones that are involved in the repair and pathology of pressure ulcers. The team used donated human tissues from pressure ulcer patients for this research.
The research team tested (R)-ND-336 in animal models, and showed that wounds improved in both size and severity in all cases, Chang said.
The researchers have completed the toxicology studies needed before applying with the FDA for an investigational new drug application for diabetic foot ulcers. Once they have applied and received approval, they can begin the phase 1 clinical trial studies, which are conducted in healthy volunteers. If the compound is approved for diabetic foot ulcers, the FDA will still require another round of trials for pressure ulcers, but the process would be shorter because the route of delivery (through the skin) is the same, Chang and Mobashery said.
The researchers said they are encouraged that the compound will work effectively and help those who suffer from pressure ulcers.
“With the use of this compound, you speed up the process of healing of the wound, whereas previously you had no tools,” Mobashery said.
The research was supported in part by the Department of Defense Therapeutic Development Award W81XWH-19-1-0493.
Other authors include Zhihong Peng, Trung T. Nguyen, Man Wan, Bowen Anderson, Mohini Mohan Konai, Valerie A. Schroeder, William R. Wolter, all from Chang’s and Mobashery’s labs at Notre Dame; Toni Page-Mayberry, Notre Dame’s Harper Cancer Research Institute, and Charles E. Peterson, from Memorial Hospital, South Bend.
Originally published by at science.nd.edu on July 22, 2022.