Researchers who have been struggling to overcome barriers to genetics-based therapies for skin disorders say cure may not be far off, particularly in light of a revolutionary advance by Italian researchers that effectively cured regions of skin in a patient with epidermolysis bullosa.

"Early clinical ... proof-of-the-principle studies clearly suggest that cell-based therapies hold promise for treatment of these currently intractable, heritable diseases," said Dr. Jouni Uitto, professor and chair of dermatology and cutaneous biology at Jefferson Medical College, Philadelphia. "My prediction is that effective treatment modalities for epidermolysis bullosa and other single-gene skin disorders will be available within a few years' time."

Dr. Michele De Luca and associates from the University of Modena and Reggio Emilia (Italy) obtained biopsies from the palms of a 36-year-old man with epidermolysis bullosa (EB) to collect epithelial stem cells. The cells were transduced using a Moloney leukemia virus-derived retroviral vector that expressed the normal full-length LAMB3 gene found to contain a single point mutation in the patient's genetic profile (Nat. Med. 2006;12:1397-402).

The patient's cells, containing the corrected protein, were then grown into nine epithelial sheets (a total area of about 500 [cm.sup.2]), which were grafted onto a denuded wound bed on the patient's thighs under local anesthesia.

The skin regenerated completely in the grafted regions and remained normal and blister free after a follow-up of 2 years, despite the fact that these areas previously harbored chronic, nonhealing lesions, Dr. Uitto said.

"The Italian study shows tremendous promise since it was one of the first ... to technically isolate cells with 'stem' features and to regenerate normal-appearing graft skin from these isolated cells," said Dr. Hensin Tsao of Harvard Medical School, Boston.

The major difference between these findings and previous tissue-engineering efforts is that the skin replacements were created using the patient's own skin stem cells and are "therefore less vulnerable to questions of immunological rejection and ethical compromise," Dr. Tsao said. "It is worth noting that robust engineered skin can also be obtained from fetal skin," he said, citing a Swiss study (Lancet 2005;366:840-2).

Although many researchers heralded the Italian study as a breakthrough, most believe that a modified approach would be necessary to treat the potentially lethal disease of skin fragility because a patient's whole body is affected, which makes graft-dependent therapy impractical.

Dr. Uitto, whose laboratory identified 8 of the 10 genes known to harbor mutations leading to EB, said protein replacement therapy may be more promising in the long run, although the Italian approach may prove valuable in treating critical nonhealing areas of skin. "It's a great advance, but I wonder whether it is the real answer," he said.

Now being studied at Stanford (Calif.) University, Jefferson Medical College, and the University of Southern California, Los Angeles, the protein approach described by Dr. Uitto relies on the administration of protein either intravenously or directly to the skin, but these studies are still in preclinical stages.

Dr. David Woodley and associates at USC recently described molecularly engineering skin fibroblasts to over-express type VII collagen, which is key to the structural integrity of the epidermal and dermal skin layers in EB. Injected into mice, these gene-corrected cells homed to wounds and promoted healing, they reported (Mol. Ther. 2007;15:628-35).

In the United Kingdom, the direct injection of skin-derived fibroblasts--from relatives and even unrelated donors--to dermis has been able to stimulate type VII collagen synthesis in humans, Dr. Uitto said.

Some researchers are studying bone marrow-derived stem cells from siblings of EB patients to see if these might induce healing once they are infused into an EB patient.

Another approach to wound healing was described by Dr. Vincent Falanga, chairman of dermatology and skin surgery at the Roger Williams Medical Center, Providence, R.I., and professor of dermatology at Boston University.

He said that researchers at the Whitehead Institute for Biomedical Research of the Massachusetts Institute of Technology, Cambridge, Mass., are investigating whether skin cells can be reengineered--not all the way back to form primitive, pluripotent stem cells, but only to the targeted, primordial state needed for a precise form of therapy.

BY BETSY BATES

Los Angeles Bureau