Biomedical Frontiers: Fall 1996, Vol.4, No.1
Genetic Therapies For Skin Disorder

Two innovative genetic therapies are helping Columbia doctors develop treatment options for epidermolysis bullosa (EB). An inherited blistering disorder, EB affects 100,000 people in the United States alone. In mild cases, the skin can blister from sli ght injury or contact, such as the simple rubbing of clothes. Severe cases result in defects in deeper layers of skin and can be fatal in the first six months of life due to loss of skin integrity and increased risk of infections.

Though experts know EB results from a defect or defects in one or more of the genes that govern structural proteins in the skin, the methods to correct these genetic errors are not yet available. Currently, the main treatment for mild cases is antibiotic creams; severe cases often require the same therapy burn victims receive but EB patients can never fully heal their skin.

Now, Dr. Angela M. Christiano, Herbert Irving Assistant Professor of Dermatology, is attacking this devastating disease on two fronts: prevention and treatment. First, she received an Irving Clinical Research Scholarship to support her work in the prevent ion of EB by preimplantation diagnosis of EB. Dr. Christiano will work closely with Dr. Mark V. Sauer, chief of reproductive endocrinology and director of assisted reproduction. "Many couples who have had one child with EB won't have another because they don't want to take the chance that the child will inherit EB," says Dr. Christiano. "Preimplantation testing will enable a couple to be certain that a child won't suffer from this debilitating and potentially fatal disease."

In preimplantation testing, a couple undergoes a cycle of in vitro fertilization, and the embryos are allowed to divide to the eight-cell stage. One of those cells is then removed for genetic testing. If the genetic tests do not indicate the presence of E B, the embryo (which continues to develop normally even after one cell is removed) is then transferred to the woman's uterus and, with luck, a pregnancy is established.

Since the exact genetic defects behind EB are different in every family, researchers must search for defects in the genome of each family that undergoes the testing, a process that takes a few weeks, says Dr. Christiano. CPMC is one of only three or four centers in the world that will offer preimplantation diagnosis.

The second front in Dr. Christiano's work involves testing gene therapy for individuals who already have EB. Using a particle accelerator or "gene gun," she will begin introducing normal genes into the skin cells of children with EB. The gun, which has lo ng been used in plant breeding and for immunizations by the military, uses microparticles of gold coated with DNA to carry the DNA through the membrane of cells cultured in the laboratory. Dr. Christiano's study, for which she received a pilot award from the CPMC Office of Clinical Trials, aims to gather preliminary evidence on whether the genes can be efficiently targeted to the correct cell layer and to determine how long they are expressed. This work could provide the foundation for the eventual applic ation of in vivo gene delivery to EB patients.

In the meantime, Ortec, a company specifically formed to produce replacement skin for people with EB, recently took up residence in the Audubon Business and Technology Center. Ortec will develop, manufacture, and market Composite Cultured Skin (CSS), repl acement skin that replicates the dermis and epidermis. Dr. Mark Eisenberg of Sydney, Australia, Ortec's founder, developed CSS after his son with born with EB.

CSS is made from specialized cells taken from infant foreskins during routine circumcisions; the cells are cultured and then grown on a cross-linked bovine collagen matrix. Ortec is conducting clinical trials of CSS and will seek FDA approval once the tri als are complete.