siRNA therapy in dominant skin and eye disorders

Incurable genetic diseases represent a major cost to the NHS, requiring specialist care costing billions per annum. RNA interference is a new Nobel prize winning technology that is suitable for treatment of a large number of genetic disorders but a major hurdle to applying this clinically is the the problem of delivery of these therapy molecules, that are slightly larger than conventional drugs, into the target tissues and organs. This programme grant focuses on a group of painful, debilitating genetic skin diseases and a related corneal eye disease, where the target tissues are very small and very accessible. The programme brings together leading researchers who uncovered the genes causing these disorders, with experts in developing new methods to deliver molecules into skin or cornea. State-of-the-art model systems will be developed to validate delivery of these new formulations into the skin and the cornea, setting the scene for taking this new therapy method into the clinic.

Despite the progress in identification of genes causing human disease, development of therapies tailored to these genetic defects has been disappointingly slow. RNAi represents a promising new means of silencing genes or mutant alleles, particularly in dominant conditions, however, a major hurdle is delivery of these agents in vivo. The palm/sole epidermis and the ocular surface epithelium are two very accessible target tissues of limited size, with obvious advantages for development of RNAi therapy. Here, we will perform identification and lead optimisation of gene-specific and mutation-specific siRNA inhibitors for keratin disorders of palmoplantar epidermis and of cornea. We will systematically compare the efficacy, specificity and stability of alternative methods of gene-specific and allele-specific silencing including morpholino oligonucleotides, locked nucleic acids (LNA) and peptide nucleic acids (PNA), relative to optimised lead siRNA inhibitors. We will develop a novel multi-target reporter gene mouse where a bioluminescence signal is targeted to footpad epidermis as a preclinical model for epidermal keratin disorders. This will be complemented by a phenotypic model of footpad hyperkeratosis. We will develop an analogous multi-target bioluminescent reporter gene mouse and a phenotypic corneal dystrophy mouse as preclinical models of a corneal keratin disorder. We will develop and optimise non-invasive methods for siRNA delivery into the skin and into the corneal epithelium, using the appropriate animal models generated. Using two different, complementary target tissues increases the chances of successful translation of this technology into human application. Solving the siRNA delivery problem opens up this technology for treatment of a wide range of incurable genetic diseases that collectively amount to a massive healthcare burden.