Update on Research on Autosomal Recessive Congenital Ichthyosis/Lamellar Ichthyosis
Professor Edel O’Toole, Centre for Cutaneous Research, Barts and the London School of Medicine and Dentistry, London (ISG MAB)
Transglutaminase 1 is an enzyme produced in the upper layers of the skin which is important for formation of the skin barrier. The skin barrier protects the body from water loss and infection. Mutations in transglutaminase 1 (TGM1) are in about 30 per cent of cases the cause for the rare form of ichthyosis, autosomal recessive congenital ichthyosis (ARCI). Individuals with ARCI due to TGM1 mutations are born as collodion babies, covered in a shiny membrane. After the collodion membrane falls off, the majority (90%) have dark-brown large scales all over, which we call lamellar ichthyosis. A small number of affected individuals also are red all over, similar to congenital ichthyosiform erythroderma (CIE) or may have features of both lamellar ichthyosis and CIE.
In October 2013, researchers in Germany and Spain described development of a topical enzyme-replacement therapy which restored TGM1 enzyme activity and corrected the skin abnormality of TGM1 deficiency1 in a skin humanized mouse model. They used engineered TGM1 protein which was encapsulated in a liposome (this is a lipid-derived carrier which allows the TGM1 into cells). They grew keratinocytes (skin cells) from patients with TGM1 mutations in the laboratory. They showed in a cell culture dish that the recombinant protein in the liposome could go into the keratinocytes and restore enzyme activity. They then put many particles of the engineered TGM1 protein in the liposome into a liposomal formulation. To test this in an in vivo (real life) situation, they used a model of TGM1 deficiency where human TGM1 deficient keratinocytes are placed on the back of an immunodeficient mouse. Because the mouse does not have a normal immune response, the keratinocytes will grow into a layer of skin. As the cells are TGM1 deficient, like those of a patient with lamellar ichthyosis, they form abnormal, thickened skin. Treatment with the formulation reduced the thickness of the skin and restored TGM1 enzyme activity towards normal. By measuring how much water was lost through the skin, the researchers were able to show that the formulation also reduced water loss, suggesting that the skin barrier was repaired. The researchers concluded that this topical approach is a promising strategy for treatment of patients with TGM1 deficiency.
Patients with lamellar ichthyosis may rightly ask how quickly might this major advance in research will help them? The answer, in my opinion, is that it is difficult to say. Further testing will be required in animal models to answer various safety questions. Then, first-in-man clinical trials will be performed in a few patients with TGM1 deficiency. It is likely that initially, only a small area of skin will be treated (perhaps about 4 inches squared- 2 X 2 inches) on one arm and the other arm will be treated with a control cream. The patients involved in the clinical trial will need to have small skin biopsies to show that the treatment has worked. If it works, then the dermatologists conducting the study may need to do further studies to work out how often the cream will need to be applied. Then, investment will be required by a pharmaceutical company to scale up the production of the cream for regular use by lots of lamellar ichthyosis patients. All of this may take up to 10 years.
Aufenvenne K, Larcher F, Hausser I, Duarte B, Oji V, Nikolenko H, Del Rio M, Dathe M, Traupe H. Topical enzyme-replacement therapy restores transglutaminase 1 activity and corrects architecture of transglutaminase-1-deficient skin grafts. Am J Hum Genet. 2013 Oct 3;93(4):620-30.
I would like to acknowledge the contribution of Prof. Dr. Heiko Traupe, Department of Dermatology, University Hospital Muenster, Muenster, Germany who commented on this summary