Skip to main content
Blizard Institute - Faculty of Medicine and Dentistry

Q&A: 3D model of harlequin ichthyosis reveals inflammatory therapeutic targets

Researchers from Queen Mary University of London, University of Cambridge, and Barts Health NHS Trust have identified new avenues for possible treatment of the genetic skin disorder harlequin ichthyosis using a 3D cell model in a new paper published in The Journal of Clinical Investigation. In this Q&A, Professor Edel O’Toole from the Blizard Institute’s Centre for Cell Biology and Cutaneous Research explains how they identified new inflammatory therapeutic targets and the wider implications of the results.

Nusrit (Nelly) Shaheen from Coventry has harlequin ichthyosis. Nelly believes in living life to the fullest. This photograph was taken during a skydive that she performed for charity in 2017.  Acknowledgement: Nusrit Shaheen.

Nusrit (Nelly) Shaheen from Coventry has harlequin ichthyosis. Nelly believes in living life to the fullest. This photograph was taken during a skydive that she performed for charity in 2017.  Acknowledgement: Nusrit Shaheen.


Harlequin ichthyosis (HI) is the most severe form of ichthyosis, a family of genetic skin disorders characterised by dry, thickened, scaly skin. It is a rare inherited disorder caused by loss of function mutations in a gene called ABCA12, which provides instructions for making a protein that is essential for the normal development of skin cells and the skin’s protective lipid barrier. Present at birth, HI causes massively thickened skin with a markedly impaired skin barrier prone to infection and water loss, and requires intensive care treatment for the new-born.

In this study, we develop a new three-dimensional cell model which mimics harlequin ichthyosis skin by using ‘molecular scissors’ called CRISPR/Cas9 to edit the genome of skin cells called keratinocytes. We use RNA sequencing to look at all the genes expressed in harlequin ichthyosis skin and show similarities with the model. Finally, we identify 2 signaling pathways involved in inflammation which are upregulated in HI skin and in the HI model- the JAK-STAT and inducible nitric oxide signaling pathways. Blocking these pathways with specific inhibitors improves the skin barrier in the HI model.


What is new about the study?

The biology of harlequin ichthyosis is poorly understood and to date no satisfactory treatment has been developed. In this study, we identify new pathways involved in HI disease pathogenesis including inducible nitric oxide and JAK/STAT signalling. We also identify a greater than 900-fold increase in IL36A gene expression in HI skin, highlighting another potential therapeutic target for future treatments.

Is there anything surprising about the results?

Although the 3D model does not contain immune cells usually present in HI skin, inhibiting nitric oxide or JAK signalling reverses the epidermal barrier defect in a cell culture dish.

Why is the study important?

There is a huge unmet need for new treatments for patients with severe ichthyosis. This study identifies four new possible avenues to treatment including some where drugs are already in clinical trials or licensed for other skin disorders; inhibiting IL36 directly, inhibiting upstream molecules including IL23, inhibiting inflammation generally using JAK inhibitors or inducible nitric oxide inhibitors.

What are the wider implications?

The treatments identified may also be useful for other severe forms of ichthyosis. We need to understand more about the epidermal barrier and the specific role of the keratinocyte, the main cell in the epidermis, versus the immune system.

More information



Back to top