UF Scientists Test Gene Therapy For Treatment Of Chronic Foot Wounds In Patients With Diabetes
GAINESVILLE, Fla.-In the newest test of gene therapy, University of Florida physicians today (8/27) applied a toothpaste-like gel to a chronic foot wound in a 67-year-old Jacksonville man with diabetes to determine if it will accelerate healing.
The creamy white preparation is genetically engineered to flood the sore with substances the body normally produces to repair skin. The patient, Kenneth Keul, developed an ulcer nearly the size of a quarter on the bottom of his left foot 10 months ago. Despite medical treatment, the sore hadn’t improved.
UF scientists are working with researchers at San Diego-based Selective Genetics Inc., the biotechnology company that developed the gel, to study whether the gene therapy approach is safe and to determine the ideal dose. The gel contains a common virus modified to carry copies of the gene responsible for making platelet-derived growth factor, which the body naturally produces to help heal wounds.
Wound repair cells are expected to migrate into the gel, take up the gene and begin churning out the growth factor, said the clinical trial’s principal investigator, UF surgery Professor Dr. David Mozingo, who directs the Wound Healing Center at the Shands at UF medical center. Researchers also will assess whether the treatment improves wound healing, determine how long the genes stay in the wounds and monitor how long the virus persists.
Each year, doctors treat nearly 3 million skin ulcers that stubbornly refuse to heal, even months after the initial injury. About 400,000 occur in patients with diabetes, thousands of whom eventually lose a foot or limb to amputation. Anything from ill-fitting shoes to stepping on something sharp can create a small wound that in these patients quickly grows into a large, open sore by day’s end, said study co-investigator Dr. Gloria A. Chin, an assistant professor of surgery at UF’s College of Medicine and chief of plastic surgery at Gainesville’s Malcom Randall Veterans Affairs Medical Center. Treating these foot ulcers racks up an estimated $1.3 billion in health-care costs a year.
“Diabetic patients often lose sensation in their feet because their nerves gradually degenerate, which makes it difficult for them to know when they have injured their feet,” said Gregory Schultz, who directs the multidisciplinary UF Institute for Wound Research. “In addition, diabetic patients frequently develop diseases of the blood vessels and capillaries in their feet, which reduce the levels of oxygen and nutrients delivered to cells in their feet. These conditions make it difficult for injuries to heal normally because diabetics often re-injure the wound and because wound cells need high levels of oxygen and nutrients to multiply and synthesize new scar tissue. So, a small, acute injury on their foot fails to heal normally and may lead to infection of the wound, which causes prolonged, elevated inflammation of the wound.”
Normally, inflammation is helpful because the white blood cells that are naturally drawn into the wound kill bacteria. They also release enzymes that remove damaged proteins that typically surround and support cells. After the damaged proteins are removed, new proteins are synthesized that form a scar.
“However, prolonged inflammation prevents the wound from healing, probably because the enzymes released by inflammatory cells also degrade the growth factors and proteins essential for wound healing,” said Schultz, also a professor of obstetrics and gynecology at UF’s College of Medicine.
At least 21 people who have diabetes-related foot ulcers will participate in the study. Initially, physicians will apply a single low-level dose of the gene therapy gel to the wounds of three patients and track them for six weeks. If no adverse effects are observed, additional patients will be enrolled and will receive higher doses. Study participants will be examined at regular intervals throughout the year following treatment and will be tracked annually for the next 15 years.
Successful studies in mice and rabbits paved the way for the current study.
“The research we and others have done strongly indicates that not enough of the growth factor is being made normally by wound cells because the molecular environment of the chronic wound destroys the growth factor before it has the chance to work,” Schultz said. “In this case, more growth factor is better, so increasing the amount of platelet-derived growth factor made by wound cells should stimulate healing.”
Another potential advantage: The approach is thought to generate continuous production of the growth factor, so daily or twice-daily applications aren’t necessary, as they would be with standard medicines, said Mozingo.
UF scientists said the adenovirus used in the study is a low-level dose compared with the amount used in other gene therapy trials, such as those testing treatments for the lung disease cystic fibrosis. Because the gel is placed on the surface of the wound, it is not widely dispersed through the bloodstream or adjacent tissues. Adverse effects are unknown, so study participants will be closely monitored for fevers, rash, abnormal liver function and other symptoms.
The U.S. Food and Drug Administration previously approved a cream that contains a recombinant protein version of platelet-derived growth factor for use on foot ulcers in patients with diabetes.
“Data from animal experiments suggest that our approach, which produces the growth factor in the wound itself for about a week after the viral vector is added, may actually be more effective than daily application of the recombinant protein version of platelet-derived growth factor to the wound,” Schultz said, adding that the new gene therapy gel also could prove to be less expensive because it would be easier to produce in mass quantities than existing medicines and possibly could be given less frequently.
Many different agents are used to treat diabetic foot ulcers, but they treat wounds very generally, Chin said.
“Nothing really targets the wound as we’re trying to do with the gene therapy involving platelet-derived growth factor,” she said. “This more specific treatment, targeting mechanisms on the molecular level, is particularly exciting.”