September 18, 2003

Topical Gene Therapy May Accelerate Healing of Diabetic Wounds

In a new test of gene therapy, physicians at the University of California, San Diego (UCSD) have applied a toothpaste-like gel to chronic foot wounds in three patients with diabetes, in an effort to accelerate healing.

The opaque white substance contains an inactivated cold virus designed to flood the sore with a gene responsible for making platelet-derived growth factor (PDGF), a compound the body normally produces to help heal wounds and repair skin.

Although there are a plethora of different agents currently used to treat diabetic foot ulcers, these applications treat wounds in a very general manner.

“There is nothing that really targets the wound as we’re trying to do with the gene therapy involving platelet-derived growth factor,” said the study’s principal investigator David Hoyt, M.D., UCSD vice chairman of the Department of Surgery and chief of trauma, burn and critical care. “This more specific treatment, targeting mechanisms on the molecular level, is particularly exciting.”

So far, three patients have undergone the procedure as part of the clinical trial at UCSD that is sponsored by San Diego-based Selective Genetics Inc. Under the direction of Hoyt and Gerit Mulder, Doctor of Podiatric Medicine (DPM), MS, director of UCSD’s Wound Treatment and Research Center in the Department of Surgery, the study will determine the therapy’s safety and ideal dose. Up to 18 people who have diabetes-related foot ulcers will participate in the clinical trial, which is believed to be the first of its kind for people with diabetes.

“Ideally, wound repair cells will utilize the gene that helps repair damaged tissue,” Hoyt said. “We will assess the effects of the treatment on wound healing and monitor how long the virus remains active in the wound.”

“Diabetics may be deficient in some of the growth factors needed for wounds to heal,” Mulder added. “Furthermore, the environment in a non-healing wound may be hostile to growth factors and other products which have been topically applied. Delivering the gene sequence to help a cell produce the needed growth factors may offer a means to overcome barriers encountered with previous treatments.”

Another potential advantage is that prolonged generation of the growth factor may eliminate daily or twice-daily applications, as occurs with currently available treatments.

In the UCSD study, physicians began by applying a single mid- to lower-level dose of the gene therapy gel to the wounds of three patients. If no adverse effects are observed, an additional 15 patients will be enrolled and will receive higher doses of the gene therapy gel. Study participants will be examined at regular intervals throughout the year following treatment.

The clinical trial utilizes Selective Genetics’ Gene-Activated Matrix (GAM) technology, that was conceived at the University of Michigan and licensed to the company. Scientists at Selective Genetics, Inc. have conducted successful animal studies in mice and rabbits that paved the way for the current study.

UCSD physicians said the adenovirus used in the clinical trial 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. The gel is placed on the surface of the wound and is not widely dispersed through the bloodstream or adjacent tissues so that the effect is expected to be primarily a local one in the wound bed. Study participants will be closely monitored for fevers, rash, abnormal liver function and other symptoms.

The U.S. Food and Drug Administration recently approved a cream that contains a recombinant version of the growth factor for use on foot ulcers in patients with diabetes.

“Data from animal experiments suggest that the new 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 applying the pre-formed growth factor to the wound,” Hoyt said. “It 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.”

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Additional Information

Each year, doctors treat nearly 3 million skin ulcers that stubbornly refuse to heal, even months after the initial injury. About 600,000 patients with skin ulcers have been estimated at any one time; thousands of these individuals may 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, may rapidly progress to a large open wound and subsequent amputation. The majority of amputations and hospitalizations for amputations in the U.S. are on diabetics who have developed infected wounds on their feet. Treating these foot ulcers costs an estimated $1.3 billion a year. With diabetes being the fastest growing disease in the U.S., the number of diabetics and subsequently, diabetic ulcers, is increasing each year.

“Diabetic patients often lose sensation in their feet, making it harder for them to know when they have an open wound or an infection,” Mulder said. “Other problems associated with diabetes may complicate or slow down the wound repair process. When the wound becomes infected or involves the bone, amputation is frequently the result.”

Keeping excessive pressure off the foot, appropriate footwear, and frequent foot examinations may help prevent the development of wounds. However, once the wound occurs, getting the wound closed as quickly as possible decreases the likelihood of an infection or limb threatening condition from arising. Bacteria, repeated injury and other factors may prevent a wound treatment from effectively working.

“Overcoming some of the barriers to wound healing but creating an optimal wound environment and making the cells do what you want them to do could have a very positive impact on getting the wound to close and help prevent amputation,” Mulder said.

 

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