The anterior corneal epithelium, composed of 4 layers of corneal epithelial cells, forms the outermost protective covering of the eye.  This epithelium specifically expresses the corneal keratins K3 and K12, which impart these cells with mechanical strength.  In the 1990s, we were the first group to discover that heterozygous dominant-negative mutations in either one of these genes leads to Meesmann epithelial corneal dystrophy (MECD), where patients present with fragility of the anterior epithelium.  Currently, we are developing small interfering RNA (siRNA) therapy for MECD and have already identified a number of highly potent, highly specific siRNAs that can knock out expression of mutant K12 mRNA and protein without affecting expression of the normal K12 gene.  Mice that are heterozygous for a null allele of K12 have no corneal dystrophy phenotype and so we are confident that this approach will be effective.  Currently, we are working on chemical modifications of the siRNA, coupled with eye drop formulations, to achieve efficient, non-invasive delivery of therapeutic siRNA to the cornea.  We are developing a range of cell culture and animal model platforms to test safety and efficacy of these therapeutics prior to clinical trials in human subjects.  In addition, we are working on a novel ex vivo gene therapy method to treat MECD and other corneal dystrophies based on small nucleolar RNA gene silencing.  Our corneal dystrophy projects are funded by The Medical Research Council and Fight for Sight. 

Our corneal dystrophy research programme benefits from close collaboration with Tara Moore, Ocular Research Group, University of Ulster, who is an honorary Senior Research Fellow in the Division of Molecular Medicine.

References:

• Irvine AD et al., (1997) Mutations in cornea-specific keratins K3 or K12 cause Meesmann's corneal dystrophy.  Nature Genetics 16: 184-187 (PubMed ID: 9171831)
• McLean WHI and Moore CBT (2011) Keratin disorders: from gene to therapy. Hum Mol Genet 20:R189-197 [Epub ahead of print Sep 10] (PubMed ID: 21890491)
• Liao H et al., (2011) Development of allele-specific therapeutic siRNA in Meesmann epithelial corneal dystrophy. PLoS ONE, in press.