Lab successes place treatment for dystrophic epidermolysis bullosa on the horizon

July 29, 2006

Research in developing gene therapy for dystrophic epidermolysis bullosa (DEB) has advanced to the stage where it could move from the laboratory into clinical trials. Unfortunately, lack of funding represents the major obstacle against taking that next step, said David T. Woodley, M.D.

Research in developing gene therapy for dystrophic epidermolysis bullosa (DEB) has advanced to the stage where it could move from the laboratory into clinical trials. Unfortunately, lack of funding represents the major obstacle against taking that next step, said David T. Woodley, M.D.

Dr. Woodley is professor and chairman of dermatology, Keck School of Medicine, University of Southern California, Los Angeles, and a pioneer in gene therapy for DEB. Speaking at the plenary session of Academy '06, he described the series of experiments that have been conducted to develop gene therapy for this devastating disease that is caused by defects in the gene encoding for type VII (anchoring fibril) collagen (C7).

Initial work focused on ex vivo gene therapy in which grafts of epidermal keratinocytes would be produced using autologous material obtained by biopsy. Those sheets would then be grafted back on to the patient. Despite achieving success in gene-correcting recessive DEB (RDEB) cells and fibroblasts with full-length C7 and in reversing the cellular EB phenotype, that approach was associated with numerous limitations, including graft fragility, the need for surgical debridement, patient immobilization and demanding wound care, as well as a high rate of graft loss.

A second strategy investigated in vivo intradermal injection gene therapy. Using cell, vector or protein therapy approaches in a hairless mouse model bearing a grafted RDEB skin equivalent, it was possible to restore expression of C7 and anchoring fibrils at the basement membrane zone (BMZ) and reverse RDEB disease features in the graft. Yet that approach also had drawbacks, in particular, its requirement for multiple painful injections.

In their most recent research, Dr. Woodley and colleagues investigated an intravenous (IV) injection approach. Administration of engineered human C7 into the tail vein of a wounded mouse showed that the protein honed to the wound site, localized in the BMZ and advanced wound healing compared with controls. Injection of gene-corrected RDEB fibroblasts was also successful in achieving C7 expression at the wound site and promoting wound healing.

Dr. Woodley notes that it is possible to produce milligram quantities of C7 that could be injected into DEB patients using the IV approach. However, clinical studies have not begun because of insufficient funds to produce the protein in a way that meets Good Manufacturing Practices standards.

"We are just a little lab and we have not been able to get Big Pharma interested in this treatment because DEB is a small orphan disease," he says.

Dr. Woodley pleaded for the AAD to partner with the Dermatology Foundation and perhaps other dermatology agencies to help fund this next step.

"This would be a great public relations move for our beloved specialty of dermatology, and we hope these organizations will find some mechanism to advance into clinical studies," he says.