Drug smooths the way to healing

New Scientist vol 178 issue 2400 - 21 June 2003, page 14

A failed cancer treatment has proved highly effective at limiting scar formation following eye surgery. Will it work elsewhere in the body too?

A DRUG originally developed to treat cancer has been found to dramatically reduce scarring of the eye. In theory, the drug should also reduce scarring in other tissues, including the skin.

Studies by a team led by Peng Tee Khaw at the Moorfields Eye Hospital in London suggest that the drug Ilomastat can reduce scarring by as much as 80 per cent, and that the healed area has a more normal structure. "This is a dramatic reduction in scar tissue," says Khaw. And since the same scarring mechanism controls the way tissues heal throughout the body, he says, the drug should reduce scarring after burns or plastic surgery too.

Scarring is at least partly due to the body's rush to try and close any wound as soon as possible to prevent infections. Cells near and in the wound release enzymes called matrix metalloproteinases, or MMPs (also called collagenases), that break down the intricate collagen matrix that holds cells together. It's a case of having to break it before you can remake it, says Khaw.

As the complex collagen structure is broken down, cells called fibroblasts migrate to the wound and the surrounding area, and actively begin to contract the tissue, a bit like gardeners compacting cuttings for the compost heap after pruning a bush. This contraction process can continue for months after an injury. The contraction helps to close the wound, but the end result is a disorderly mass of collagen that forms disfiguring and sometimes painful scar tissue.

"Contraction is one of the greatest enemies of tissue regeneration," says Khaw. It is a particularly big problem after eye operations, he adds, because the precise positioning of collagen proteins in the matrix affects the optical properties.

Various drugs are already used to reduce scarring of the eye, including anti-cancer drugs that trigger cell suicide, or apoptosis. But these drugs are far from ideal, since by killing cells they prevent healing as well as scarring, and can occasionally cause complications.

It has long been suspected that MMPs played an important role in wound healing, so Khaw's team decided to test the effects of various MMP inhibitors. These inhibitors, including Ilomastat, were developed to treat cancer, as it was thought that preventing the breakdown of the collagen matrix might stop cancerous cells migrating around the body. But the drugs were not effective.

Tests on tissue grown in culture, however, show that Ilomastat can reduce contractile scarring by up to 80 per cent. And when Khaw's team injected it into the inner lining of the eyes of rabbits after they had undergone a type of surgery used to treat glaucoma, there was also a dramatic reduction in scarring.

"We appear to be regulating the way the individual fibroblasts remodel and migrate within the matrix," Khaw says. "The tissue appears to be healthy and functioning." The team is now looking for partners to develop the method further and get it to human trials.

Other scarring experts still need convincing. "I don't think it will transfer beyond eyes," says Mark Ferguson at Manchester University. In the past, he says, other groups have tried using MMP inhibitors on the skin but they found that it actually prevents healing.

But Khaw says that these researchers applied MMP inhibitors directly to the surface of the skin, even though the contraction that leads to scarring occurs beneath the outermost layer of skin. His method involves injecting Ilomastat into the underlying layers where the contraction occurs.

Timing is also crucial, Khaw says. If the inhibitors are applied too soon, before contraction has started, then healing is indeed impaired. Recent studies of mice in which one or more of the genes that code for MMPs have been "knocked out" have also revealed noticeable differences in the healing process, Khaw adds - further evidence that that MMPs play a key role in healing in all tissues.

Duncan Graham-Rowe