Corneal dystrophy

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 gene silencing 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.  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.  Our corneal dystrophy projects are funded by The Medical Research Council and Fight for Sight

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, Irvine AD, MacEwen CJ, Weed KH, Porter L, Corden LD, Gibson AB, Moore JE, Smith FJD, McLean WHI* and Moore CBT (2011) Development of allele-specific therapeutic siRNA in Meesmann epithelial corneal dystrophy. PLoS ONE 6:e28582 [Epub ahead of print 12th Dec 2011] doi:10.1371/journal.pone.0028582
  • Allen EHA et al., (2012) Allele-specific siRNA silencing for the common keratin 12 founder mutation in Meesmann epithelial corneal dystrophy.  Invest Ophthalmol Vis Sci [Epub ahead of print Dec 11, 2012] PubMed ID: 23233254