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Back To Vidyya Antisense Drugs Topically Delivered To Skin Inhibit Gene Associated With Psoriasis:

Study Published in The Journal of Investigative Dermatology

Scientists at Isis Pharmaceuticals have demonstrated that antisense drugs when delivered topically to the skin, in a cream formulation, effectively inhibit the production of Intracelluar Adhesion Molecule (ICAM-1), a gene associated with psoriasis and other inflammatory diseases of the skin. Data from the pre-clinical study was published in a recent issue of The Journal of Investigative Dermatology. The study demonstrated antisense inhibition of ICAM-1 gene expression and achievement of significant and prolonged drug concentration in skin. The findings of this research are the basis for a Phase II clinical trial of ISIS 2302, an antisense inhibitor of ICAM-1, to treat patients with psoriasis.

In the study, researchers grafted human skin onto the backs of SCID (severely compromised immunodeficient) mice. Scientists induced skin inflammation to stimulate ICAM-1 expression, and the mice received ISIS 2302 through topical application or intravenous injection. Following topical administration of ISIS 2302, investigators observed a significant reduction in ICAM-1 expression. Topical administration of ISIS 2302 delivered high concentrations of drug in both the epidermis and the dermis, key sites within the skin where inflammation is present in disease. Further, researchers found that skin quickly absorbed the cream formulation of ISIS 2302 and that drug levels remained high for a sustained period of time.

"This research is very promising as penetrating the protective layer of the epidermis and obtaining significant drug concentrations in the dermis has been a challenge in developing topical treatments. A topical cream with the potential to deliver a high level of drug beyond the epidermis and that specifically targets a prime trigger of skin inflammation, ICAM-1, would be a meaningful treatment for people affected by inflammatory skin diseases, such as psoriasis," said Gerald Krueger, M.D., of the University of Utah School of Medicine Division of Dermatology.

Data reported in this publication support Isis' dermatology program, which currently has ISIS 2302 in a Phase II trial for the treatment of psoriasis and ISIS 104838 in pre-clinical development, also for psoriasis. In early clinical trials, ISIS 2302 delivered intravenously showed modest evidence of activity in psoriasis with only small amounts of the drug concentrating in the skin. Based on these results, Isis created a more convenient topical cream formulation of ISIS 2302, which enables higher concentrations of drug to be delivered directly to the skin.

"We learned from previous investigations that intravenous administration delivered less than ideal amounts of antisense drug to the right inflammatory targets within the skin. In this study we demonstrate that through topical application, we achieve a 4,000-fold increase in drug accumulation in the epidermis and 150-fold increase in the dermis, further expanding the clinical utility of this technology," said C. Frank Bennett, Ph.D., Vice President of Antisense Research. "This research has helped to shape and guide the Company's dermatology program, and we are enthusiastic about the potential of giving antisense drugs in a route of administration preferable to clinicians and to people with inflammatory diseases of the skin."

ICAM-1 is a cell adhesion molecule that plays a pivotal role in the inflammatory process. Expression of ICAM-1 is markedly increased in cells present in both the epidermis and dermis in psoriatic plaques and is believed to maintain the inflammatory processes that cause psoriasis. According to the National Psoriasis Foundation, it is estimated that over seven million Americans (2.6 percent) have psoriasis, with more than 150,000 new cases reported each year.

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Editor: Susan K. Boyer, RN
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