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.

This programme is aimed at developing therapy for dominantly inherited keratinizing disorders. This group of hereditary disorders mainly causes cell fragility in specific differentiated cell compartments of the epidermis but some also affect some epithelial barrier tissues, such as the anterior corneal epithelium. Keratinizing 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 result in lifelong, very painful, skin blistering and thickening. The prototypic disease is epidermolysis bullosa simplex (EBS), an autosomal dominant skin blistering disorder, with 5000 cases in the UK. In Meesmann epithelial corneal dystrophy, the corneal epithelium is affected instead, leading to visual impairment and eye pain.

The underlying problem in this group of conditions is dominant-negative interference resulting from missense or small in-frame insertion/deletion mutations in keratin intermediate filament proteins or related proteins.

Here, we will develop a highly specialised type antisense oligonucleotide (or ASO) that can inhibit the mutant allele, without altering the normal allele. A major hurdle to applying this technology clinically is that ASOs are difficult to deliver in vivo. A US-based company, Wave Life Sciences, has recently developed a new form of ASO chemistry which is more potent, has single-nucleotide specificity and shows enhanced bioavailability The Dundee group has developed a a whole range of bioluminescent animal models expressing luciferase in specific epithelial and epidermal compartments to test ASO delivery. We have also recently developed a proprietary system for longer term and much more functional organ culture of mammalian skin. In addition to developing ASO delivery, we will build case collections of well genotyped and phenotyped patients in readiness for future clinical trials of our ASO technology or other therapeutic approaches.

This research programme is aimed to benefit an important area of unmet medical need, namely, a large group incurable and currently untreatable inherited disorders affecting the epidermis and outmost protective layers of the eye. In a broader sense, scientific and technical hurdles overcome in the course of this project might later be of benefit outside of dermatology and ophthalmology, by being applied to hundreds of genetic disorders of other organ systems where the underlying mechanism is similar.

The main focus of the programme is development of treatment for three prototypic genetic diseases each of which has some advantage in terms of tractability. There are - the hereditary skin blistering disease epidermolysis bullosa simplex (EBS), that affects about 5000 people in the UK; the very painful debilitating skin disorder pachyonychia congentia (PC), affecting about 500 people in the UK; and Meesmann epithelial corneal dystrophy, an inherited defect of the cornea, which affects some hundreds of British patients.

In each of these conditions (and hundreds of other inherited diseases), the underlying disease mechanism is dominant-negative interference, whereby a single copy of a mutated gene is able to overcome the normal copy of the gene present, resulting in the disease pathology. Here, we aim to develop a means of silencing only the defective copy of the disease-causing gene without affecting the normal copy. There is a substantial body of evidence that this will be an effective treatment. The system we will employ, in partnership with our industrial collaborator Wave Life Sciences, is an advanced form of antisense technology - a system capable of discriminating very minor differences between copies of genes and specifically silencing the desired copy.

A major hurdle in applying this technology to dermatology and ophthalmology diseases is lack of an effective non-invasive method to get antisense molecules into the epidermis or cornea of the eye. A significant proportion of this programme is aimed at developing and optimising delivery into these tissues.

If successful, this system could be extended to other skin and eye disorders, as well as hundreds of other genetic conditions. The system could also be readily adapted to treat common conditions of the skin such as eczema, psoriasis and importantly, skin cancers, by silencing genes that are critically important drivers of those diseases.

Thus, this programme has great potential benefit very large numbers of individuals by bringing about treatments for distressing and debilitating conditions that cannot currently be treated.