Repairing UV damage to Skin

November 1, 2005

After exposure to UV, "Keratinocytes send out immune suppressing signals [the cytokine IL-10] and antigen presenting cells are chased out of the skin," Dr. Yarosh explains.

Ultraviolet (UV) rays can damage skin in two ways, by forming the cyclobutane pyrimidine dimer (CPD) in cell DNA that can lead to skin cancer, and by actively suppressing the immune response in skin, says Daniel B. Yarosh, Ph.D.

Dr. Yarosh is a molecular biologist and former researcher at the National Cancer Institute who formed Freeport, N.Y.-based Applied Genetics, Inc. in 1985 (changing the name to AGI Dermatics in 1998) and serves as its president.

Dimericine (AGI Dermatics), a DNA repair enzyme in a liposome lotion, can speed up the recovery process of UV damaged skin.

The study recruited people who were allergic to nickel, about 20 percent of the population, and irradiated them with a solar simulating light on a spot on their lower backs, then challenged them with exposure to nickel sulfate. Participants could mount an allergic response to nickel elsewhere on their body but not where the skin had been irradiated.

After exposure to UV, "Keratinocytes send out immune suppressing signals (the cytokine IL-10) and antigen presenting cells are chased out of the skin," Dr. Yarosh explains.

"When they applied Dimericine to spots after irradiation, and then later challenged with nickel, the skin showed an allergic reaction. The cells were able to mount an immune response."

Dimericine contains T4 endonuclease V, which is a recombinant protein that was identified in a bacteriophage. It is able to bind to DNA and searches for DNA damage.

"If there is no DNA damage, it doesn't do anything to the cell. When it finds damage, it makes a break in the strand of DNA at the site of the damage and that triggers a repair response where the piece of DNA that is damaged is cut out and replaced."

Immune system, DNA repair

"If you have a sunburn, normally it takes about 24 hours to remove half the damage, but with Dimericine it takes somewhere between four and six hours. By increasing the rate of repair, the skin and the immune system are protected. When the damage goes away, the stress signals and the release of cytokines go down," Dr. Yarosh says.

Dr. Yarosh then turned to the effects of immune suppression on DNA repair. Renal transplant patients have very high rates of skin cancer that begins about four years post-transplantation and by year 20, about 80 percent of the patients have experienced skin cancer. It is believed to be associated with the immune suppressive drugs taken to prevent rejection of the organ; with less immune surveillance to rein in mutations, skin cancers grow out.

"We asked a second question: do these drugs also affect DNA repair?"

Working with cell cultures that had been irradiated, then dosed with drugs used post-transplant to suppress organ rejection, Dr. Yarosh found that DNA repair was reduced. The drugs also suppressed levels of the p53 tumor suppressing protein.

"Anytime you get that combination, it's a prescription for skin cancer."

Trials after renal transplantation

The University of Alabama, Birmingham, is currently recruiting renal transplant patients, who are at least four years post-transplant and have already had skin cancer, into a phase IIB double-blind placebo-controlled trial to see if use of Dimericine can lower their rates of skin cancer. The study is sponsored by the National Cancer Institute, with AGI Dermatics supplying the drug.

The company has completed and published results on a phase 3 trial in patients with the rare disease xeroderma pigmentosum and are about to initiate a phase 2 trial in the at-risk population of those who already have had skin cancer. A commercial product is at least three to five years down the road.

Dr. Yarosh compares this approach with currently available immune response modifiers. He says those therapies try to heighten activation of a present and intact immune function.