Developing new medicines for incurable genetic skin diseases

Therapy Development in DGEM


DGEM investigators are at the forefront of research to identify new, more effective treatments for rare skin diseases such as epidermolysis bullosa (EB), pachyonychia congenita, various forms of keratoderma and common conditions such as skin cancer or eczema.


Gene silencing therapy for skin and eye disorders

In the dominantly inherited genetic disorders where the underlying mechanism is dominant-negative protein interference (such as most inherited keratin gene disorders), an attractive therapy strategy is to selectively inhibit expression of the mutant allele, allowing the normal allele to function.

In families with a rare recessive type of the skin blistering disorder epidermolysis bullosa simplex, we have previously shown that heterozygous carriers of a null mutation in the keratin K14 gene have perfectly normal skin (Rugg et al., 1994).  Furthermore, we have shown that knocking out one copy of a keratin gene in mouse does not affect the structure and function of the epidermis (Fu et al., 2014).  These studies in both mouse and human provide proof-of-concept for our therapy strategy of silencing the dominant-negative mutant allele and allowing the single normal allele to function. 

There are at least two methods of inhibiting disease-causing mutant alleles of genes: (i) small interfering RNA (siRNA, a type of RNA interference or RNAi); and (ii) antisense oligonucleotides (ASOs).  Until fairly recently, only siRNA seemed capable of targeting single nucleotide variants such as those found in keratins and other skin disease genes, however, recent major advances in ASO chemistry means that these molecules are now capable of inhibiting point mutants. 

The majority of keratin mutations are single point mutations leading to amino acid substitutions.  Using a medium throughput assay system, we systematically screen all possible small-interfering RNA (siRNA) or antisense oligonucleotide (ASO) molecules against wild-type and mutant reporter gene constructs to identify those positions where the mutant allele is potently and selectively inhibited.  These inhibitors are then taken through secondary screening using biochemical and functional assays to arrive at lead molecules for clinical development. 

Currently, we are exploring non-invasive methods to deliver siRNA into the epidermis and into the cornea, using organotypic culture and animal model systems, including live-animal imaging.  Our multidisciplinary oligonucletide skin delivery programme, includes self-delivery chemical modifications of the RNA molecules, topical formulation chemistry and biomedical physics applications, such as ultrasound and laser-assisted drug delivery.

We have reported the first therapeutic siRNAs for the skin blistering disorder epidermolysis bullosa simplex (Atkinson et al., 2011) and for the inherited eye disease Meesmann Epithelial Corneal Dystrophy (Liao et al., 2011). 

We also reported the development of mutation-specific siRNA aimed mutations in the keratin K9 gene causing the palm and sole skin blistering/thickening disease epidermolytic palmoplantar keratoderma (Leslie-Pedrioli et al., 2012). 

The image to the right shows typical mutation-specific inhibitor development.  The graph at the top shows that increasing the concentration of a mutation-specific siRNA leads to reduction of mutant K9 gene expression (K9-MUT) but has little effect on normal K9 gene expression (K9-WT).  Below, triplicate experiments show near-complete loss of the green-labelled disease-causing K9 mutant protein from cells treated with one of these potent, highly specific K9 siRNAs (siMUT-13), with little or no effect on normal K9 protein (red-labelled). A non-targeting control siRNA does not affect normal or mutant K9 (negative control). 

We now have similar data showing inhibition of mutant alleles using ASOs, which are smaller molecules that should more easily penetrate the epidermis.  In 2015, we signed a partnership with Wave Life Sciences, Cambridge, Massachusetts, USA to develop and deliver ASO therapy for keratin disorders.
These and other mutation-specific inhibitors for a number of keratin disorders are in further development with the aim of carrying out clinical trials over the next few years.


  • Atkinson SD, McGilligan VE, Liao H, Szeverenyi I, Smith FJD, Moore CBT, McLean WHI (2011) Development of allele-specific therapeutic siRNA for keratin 5 mutations in epidermolysis bullosa simplex. J Invest Dermatol 131:2079-2086 [Epub ahead of print Jun 30] (PubMed ID: 21716320)
  • Fu DJ, Thomson C, Lunny DP, Dopping-Hepenstal PJ, McGrath JA, Smith FJD, McLean WHI and Leslie Pedrioli DM (2014) Keratin 9 is Required for the Structural Integrity and Terminal Differentiation of Palmoplantar Epidermis. J Invest Dermatol 134:754-763 [Epub ahead of print Aug 20, 2013] (PubMed ID: 23962810)
  • Leachman SA et al., (2010) First-in-human Mutation-targeted siRNA Phase Ib Trial of an Inherited Skin Disorder. Molecular Therapy 8:442-446 (PubMed ID: 19935778)
  • Smith FJD et al., (2008) Development of therapeutic siRNAs for pachyonychia congenita.  J Invest Dermatol 128:50-58 (PubMed ID: 17762855)
  • Leslie Pedrioli DM,  Fu DJ, Gonzalez-Gonzalez E, Contag CH, Kaspar RL, Smith FJD, McLean WHI (2012) Generic and Personalized RNAi-Based Therapeutics for a Dominant-Negative Epidermal Fragility Disorder. J Invest Dermatol 132:1627-1635 [Epub ahead of print 8th Mar 2012] (PubMed ID: 22402445)
  • Hickerson RP et al., (2008).  Single nucleotide-specific siRNA targeting of mutant keratin 6a responsible for the dominant-negative skin disorder pachyonychia congenita.  J Invest Dermatol 128:594-605 (PubMed ID: 17914454)
  • 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
  • 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)
  • Rugg EL, McLean WHI, Lane EB, Pitera R, McMillan JR, Dopping-Hepenstal PJC, Navsaria HA, Leigh IM and Eady RAJ (1994) A functional 'knock out' of human keratin 14. Genes Dev 8: 2563-2573 (PubMed ID: 7525407)


Cutaneous Drug Discovery

One of the key strategic aims of the Dermatology and Genetic Medicine group is to translate our discoveries in genetics into new improved treatments for patients.  In close collaboration with the Drug Discovery Unit, we are actively pursuing a number of small molecule drug discovery projects aimed at treatment of genetic disorders, particularly those affecting the skin.

The first of these is aimed at the rare keratinizing skin disorder pachyonychia congenita (PC), which is caused by mutations in any one of the genes encoding keratins K6a, K6b, K6c, K16 or K17.  From a high-throughput screen of a small molecule library, we showed that surprisingly, the cholesterol-lowering statins show inhibitory effects on the expression of PC-related keratin genes (Zhao et al., 2011).  This work, funded by the patient organization PC Project, is now at the stage of advanced preclinical testing. 

Secondly, we have developed novel chemical compounds that may be able to benefit patients with certain types of genetic mutations across a wide range of genetic disorders.  This project, originally financed by an MRC Project grant, further MRC DPFS funding and GlaxoSmithKline (GSK), is currently being developed in partnership with Pfizer.

Thirdly, we have identified small molecules capable of up-regulating expression of the human filaggrin gene, as a therapeutic strategy for eczema.  About 10% of the population are heterozygous carriers of a filaggrin loss-of-function mutation and therefore would benefit from increased filaggrin protein expression from the remaining normal copy of the gene.  This work, initially funded by MRC, is at the stage of medicinal chemistry and validation in animal models. 


  • Lane EB and McLean WHI (2008).  Broken bricks and cracked mortar – epidermal diseases resulting from genetic abnormalities.  Drug Discov Today: Disease Mechanisms, 5: 393-401.
  • McElroy SP, Nomura T, Torrie LS, Warbrick E, Gartner U, Wood G and McLean WHI (2013) A lack of premature termination codon read-through efficacy of PTC124 (Ataluren) in a diverse array of reporter assays. PLoS Biol 11(6):e1001593 [Epub Jun 25, 2013]. (PubMed ID: 23824517)
  • Zhao Y et al., (2011) Statins downregulate K6a promoter activity: a possible therapeutic avenue for pachyonychia congenita. J Invest Dermatol. 131: 1045-1052 (PubMed ID: 21390048)