Therapeutic avenues for ARCI by targeting common pathways of hyperkeratosis (2014)
Dr. Ryan O’Shaughnessy received $50,000 from the FIRST Research Grant Program to continue his work in targeting the scaling pathways in ichthyosis. The research specifically focuses on understanding the mechanisms that cause scaling, and subsequently increasing the options for treatment.
As explained by Dr. O’Shaughnessy, “Hyperkeratosis, or scaling, is a very common symptom in skin disease, with around 150 genetic ichthyosis and ichthyosis-related skin diseases leading to this thickening of the outermost layer of the skin. In many skin diseases this scaling is the most outwardly visible effect of the disease, and the one that patients would most want to treat. Current treatments for hyperkeratosis such as retinoids, although effective, are used without a full understanding of the molecular machinery behind the process. By better understanding the basis for scaling ("molecular mechanism") in ichthyosis, more directed protein or gene therapies could be developed that benefit patients, regardless of their specific genetic defect. Also, if possible, it would be particularly attractive to find therapeutic targets that already have a range of drugs that could be rapidly re-tooled to treat ichthyosis, providing dermatologists multiple therapeutic options to treat ichthyosis beyond the first-line treatment of retinoids.
Our previous studies on autosomal recessive congenital ichthyosis, the most severe form of ichthyosis, have identified key components of the molecular machinery that causes scaling. We have already determined a key cellular signal, interleukin-1 alpha, which plays a critical role in the process. We think this signaling pathway represents an attractive new target in the treatment of scaling. In this project, we will test three different drugs, including retinoids and aspirin, on their ability to reduce interleukin-1 alpha signaling and skin scaling in skin cells and 3D reconstructed skin models from ichthyosis patients. The drugs are tested either on their own or in combination. Our longterm aims of this research are to more fully understand the mechanisms that cause scaling and, as a result, to increase the options available to treat scaling, not only in ichthyosis, but potentially in a wide range of skin diseases.”