MICA: Delivering gene silencing therapy to the epidermis and ocular surface

This research programme is aimed at developing treatments for inherited skin and eye disorders that are currently untreatable and incurable at the present time. These disorders are collectively rare but when grouped together, affect about 1 in 5000 people or about 12,000 individuals in the UK alone. These conditions are characterised by fragility of cells within the epidermis, the outermost part of the skin, and result in lifelong, very painful, skin blistering and thickening. In one disease, the outermost layers of cells covering of eye (part of the cornea) are affected instead, leading to visual impairment and eye pain. These diseases have an onset at birth or early infancy and are a lifelong burden to the patients, their families and carers. The cost of lifelong symptomatic treatment of these patients represents a significant financial burden on the NHS, although there is no truly effective treatment, only dressings and pain management. The underlying problem in this group of conditions is a particular type of mutation or genetic "spelling mistake" in genes whose main function is to give cells mechanical strength. Everyone has two copies of most genes. In these particular genetic skin and eye disorders, one of these copies is normal but the other one is defective. Unfortunately, the defective gene is able to overcome the normal gene and prevent the normal one from doing its job properly. This mechanism, called dominant-negative interference, underlies very many of these important skin and eye disorders. Here, we will develop a highly specialised type of therapy molecule (called an antisense oligonucleotide or ASO) that can enter the affected cells of the skin or eye and "switch off" the mutant gene, without altering the normal gene. This will allow the normal gene to function correctly and greatly alleviate the symptoms of the disease or cure it completely. A major hurdle to applying this technology clinically is that ASOs are difficult to get into the cells of the skin and the eye. A US-based company, Wave Life Sciences, has recently developed a new form of ASO which we have reason to believe will be easier to deliver to the epidermis and the cornea than previous versions. In Dundee, we have developed a number of highly sophisticated technology platforms for studying and refining the delivery of ASO into the skin and cornea. This programme represents a close collaboration with Wave Life Sciences to bring together their expertise with the Dundee group's experience in dermatology and ophthalmology to move this exciting, potentially curative therapy technology, into clinical application. This will be of direct benefit to patients with rare diseases but if successful, this technology could be used to treat common skin conditions such as eczema, psoriasis and acne, as well as common and life-threatening skin cancers. The technology could also be readily adapted to treat other genetic conditions affecting organs other than the skin or eye.