Once upon a time, psoriasis primarily was thought of as a skin disease, caused by excess proliferation of keratinocytes, a type of skin cell.

Then, research showed that a mis-regulated immune system - specifically, helper T cells - is an important contributor to the development of psoriasis. Today, most psoriasis treatments target T cells, and those that are aimed at keratinocytes usually are nonspecific, targeting proliferating cells.

But there's been new research.

"What is exciting about our data," said John DiGiovanni, chairman of the department of carcinogenesis and director of the Science Park-Research Division at the University of Texas M.D. Anderson Cancer Center, "is that it brings both ideas together."

Those data finger the signal transduction protein STAT3, which also has been implicated in some cancers (another disease marked by excess cell proliferation) as a possible missing link between skin and immunological events in psoriasis. They are published in the January 2005 early online issue of Nature Medicine. The M.D. Anderson researchers collaborated with colleagues from Louisiana State University in Shreveport, Osaka University Graduate School in Japan and Loyola University in Chicago.

The researchers first observed, via immunohistochemical analyses, that STAT3 is activated in psoriatic skin lesions, but not in several other inflammatory skin diseases. They then generated transgenic mice with a constitutively active form of STAT3. Those mice developed psoriatic lesions within a few weeks of birth.

Psoriasis bears some resemblance to the process of wound healing, and so the response to a wound could provide clues to psoriasis researchers. When the mice underwent repeated application and removal of transparent tape to the skin (a procedure known as tape stripping), the resulting wounds in the transgenic mice, but not in control mice, resembled psoriatic lesions. Blood vessels under the wounded skin also were increased in number and more dilated than in control mice.

To investigate the interplay between STAT3 and T cells, the scientists next grafted skin from the transgenic mice onto athymic mice, which do not produce T cells. In those mice, tape stripping of the skin grafts alone did not lead to psoriatic lesions, but tape stripping in combination with injection of activated T cells did. Grafted skin from control mice did not develop psoriasis-like characteristics, even after the injection of activated T cells. In combination, those data show the need for both STAT3 in the skin and T cells (which, in further experiments, were shown to be CD4+ "helper" T cells) for the development of psoriatic lesions.

In a final experiment, the researchers blocked STAT3 activation after tape stripping through decoy DNA. Decoys are double-stranded DNA oligonucleotides that are very similar to the DNA sequence STAT3 normally would bind to activate its target genes. Given sufficient amounts of decoy DNA in a cell, the available STAT3 essentially is mopped up, binding to the decoy instead of the gene promoter. When the scientists pretreated transgenic mice with topical application of decoy DNA prior to tape stripping, those mice did not develop psoriatic lesions, while control decoy-treated mice did. Decoy DNA also was able to reverse some pre-existing lesions.

What Does A Model Need To Model?

The mouse model, which is based on inducing psoriasis via a defect in keratinocytes, does not address whether in clinical psoriasis the original defect lies in T cells or skin cells. However, DiGiovanni told BioWorld Today the chicken-and-egg question is something of a red herring in terms of its clinical relevance.

"I'm not sure it's necessary to replicate the timing" of psoriasis, as long as the model leads to relevant clinical targets, he said. Instead, what is important is that "this gives us a therapeutic target to look at in the keratinocytes."

DiGiovanni is interested in pursuing the clinical implications of his work. The researchers are planning to test their decoy DNA in a human skin graft model, a project that DiGiovanni described as being "in the early planning stages." Since human skin is much thicker than mouse skin, it remains to be seen whether there are problems with the topical delivery of DNA decoys to human skin. But "if we can use the decoy topically on human skin, we would immediately start working toward a clinical trial," DiGiovanni said.

He added, "I am very interested in industrial collaborations. Any company that has inhibitors for STAT3 that I'm not aware of - and I'm sure there are plenty of them - we are open [to collaborating], because we have the models to test them." He already has been contacted by a variety of companies, though there are no formal industrial collaboration agreements yet.

Inhibiting Keratinocytes Part 2: Try Benzodiazepines

Another recent paper also reports on targeting skin cells to treat psoriasis. The compound in question is a benzodiazepine, but it binds to neither central nor peripheral benzodiazepine receptors. Instead, it appears to work by binding to mitochondria.

"Think of benzodiazepine as a scaffold," said Gary Glick, professor of chemistry and biological chemistry at the University of Michigan Medical School. It's the side groups, or attachments to that scaffold, that determine binding, which is why Bz-423 has no anxiolytic properties whatsoever.

The compound was tested first against lupus; now in new studies, published in the Dec. 2, 2004, issue of the Journal of Pharmacology and Experimental Therapeutics, Glick and his colleagues reported that in cultured skin biopsies, Bz-423 preferentially targeted proliferating keratinocytes and inhibited their growth.

Glick did not want to give details about the compound's mechanism of action, citing other publications now under peer review, but he told BioWorld Today that the compound appears to have a novel and targeted mechanism to control cell growth and proliferation that could be used in a variety of ways. The compound is under commercial development by GMP Immunotherapeutics Inc. That company is a subsidiary of Fort Lauderdale, Fla.-based GMP Companies Inc., described by Glick as an "accelerator" - the company in-licenses and develops pharmaceutical and medical device technologies.