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
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.