Ichthyosis Research (2001/2002)
John McGrath, MD, FRCP, Professor of Molecular Dermatology at St. John's Institute of Dermatology at St. Thomas' Hospital, London, England
The last few years have seen considerable advances in our understanding of most of the major forms of ichthyosis. A few years ago knowledge was limited to a number of clinical descriptions, many of which were rather verbose and imprecise. Now, however, we are starting to get a much better appreciation of the specific inherited biochemical, structural and genetic abnormalities that change the function of the skin barrier resulting in scaling, redness, water loss or itching, skin thickening or peeling.
Discovering the underlying genetic cause of a particular form of ichthyosis is the first and crucial step in developing and applying technology to help affected people and their families. Precise gene abnormalities have now been discovered in several of the ichthyoses, although the cause of the most common form of inherited ichthyosis, ichthyosis vulgaris, remains a mystery.
For those conditions in which the genes are known, the immediate benefits relate to being able to establish a precise diagnosis and to improving genetic counseling, which may also include discussions about antenatal diagnosis. In the longer term, discovering an abnormal gene has implications for the development of newer forms of treatment, including gene therapy. Almost 5 years ago, a group from Stanford University in California reported their initial experiments aimed at developing gene therapy for lamellar ichthyosis. Their findings, published in the journal Nature Medicine, described engineering copies of the transglutaminase 1 gene (one of the abnormal genes in lamellar ichthyosis - there are others) and inserting the gene into skin cells (ketatinocytes) taken from a patient with lamellar ichthyosis. These cells were then grafted onto a mouse that lacked an intact immune system, so it would not reject the human tissue, and the behavior of the new, modified skin was observed. Dramatic improvements of the function of the skin were seen with elimination of the skin scaling and restoration of the epidermal barrier function with less water loss.
Unfortunately, these exciting initial observations could not be maintained and the new gene function was lost after a few weeks. Since that time, this group of researchers and several others from around the world, have continued to try to refine the methods of delivery of new genes into keratinocytes. Efforts have focused on the delivery package (e.g. modified forms of viruses capable of getting into the cells in high numbers), the keratinocyte target (i.e. “stem cells” that give rise to all the other cells in the epidermis), and regulating the expression of genes (control switches for turning genes on or off, up or down). Considerable work has also gone into analyzing the safety of gene modification strategies as well as what happens to the human immune system if it is suddenly exposed to the product of a new gene that it has never met before. All of these are major considerations when it comes to the design of successful gene therapy approaches. The science may still be in the laboratory, but further “mouse models” are already emerging and, statutory regulation permitting, human trials are now a more realistic proposition than they have been for some time.
So, the progress to report is that researchers now have a much better handle on the causes of most forms of ichthyosis and that we should now anticipate further reports of gene therapy studies. Most of these will represent minor advances, taking the science forward step-by-step and learning more about how newly transferred genes behave, but gradually we will get closer and closer towards those studies that have a major impact on ichthyosis sufferers and their families.