Publications by authors named "Wh Irwin McLean"

4 Publications

  • Page 1 of 1

Changes in nano-mechanical properties of human epidermal cornified cells in children with atopic dermatitis.

Wellcome Open Res 2020 17;5:97. Epub 2020 Jul 17.

Dermatology, Children's Health Ireland at Crumlin, Dublin, Ireland.

 Impaired skin barrier is an important etiological factor in atopic dermatitis (AD). The structural protein filaggrin (FLG) plays a major role in maintenance of the competent skin barrier and its deficiency is associated with enhanced susceptibility to mechanical injury. Here we examined biomechanical characteristics of the corneocytes in children with AD and healthy controls. We recruited 20 children with AD and 7 healthy children. They were genotyped for filaggrin gene ( ) loss-of-function mutations. Stratum corneum was collected from clinically unaffected skin by adhesive tapes. Cell stiffness (apparent elastic modulus, Ea) was determined by atomic force microscopy and filaggrin degradation products (NMF) by liquid chromatography. Skin barrier function was assessed through trans-epidermal water loss (TEWL) and disease severity by the SCORing Atopic Dermatitis (SCORAD) tool. Corneocytes collected from AD patients showed a decreased elastic modulus which was strongly correlated with NMF and TEWL, but not with SCORAD. As compared with healthy controls, AD patients had reduced TEWL and NMF levels regardless of mutations. NMF was strongly correlated with TEWL. Our findings demonstrate that AD patients have decreased corneocyte stiffness which correlates with reduced levels of filaggrin degradation products, NMF and skin barrier function. Altered mechanical properties of the corneocytes likely contribute to the loss of mechanical integrity of the SC and to reduced skin barrier function in AD.
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http://dx.doi.org/10.12688/wellcomeopenres.15729.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477645PMC
July 2020

Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis.

Nat Genet 2015 Dec 19;47(12):1449-1456. Epub 2015 Oct 19.

Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland.

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis.
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http://dx.doi.org/10.1038/ng.3424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753676PMC
December 2015

First-in-human mutation-targeted siRNA phase Ib trial of an inherited skin disorder.

Mol Ther 2010 Feb 24;18(2):442-6. Epub 2009 Nov 24.

Department of Dermatology, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112-5550, USA.

The rare skin disorder pachyonychia congenita (PC) is an autosomal dominant syndrome that includes a disabling plantar keratoderma for which no satisfactory treatment is currently available. We have completed a phase Ib clinical trial for treatment of PC utilizing the first short-interfering RNA (siRNA)-based therapeutic for skin. This siRNA, called TD101, specifically and potently targets the keratin 6a (K6a) N171K mutant mRNA without affecting wild-type K6a mRNA. The safety and efficacy of TD101 was tested in a single-patient 17-week, prospective, double-blind, split-body, vehicle-controlled, dose-escalation trial. Randomly assigned solutions of TD101 or vehicle control were injected in symmetric plantar calluses on opposite feet. No adverse events occurred during the trial or in the 3-month washout period. Subjective patient assessment and physician clinical efficacy measures revealed regression of callus on the siRNA-treated, but not on the vehicle-treated foot. This trial represents the first time that siRNA has been used in a clinical setting to target a mutant gene or a genetic disorder, and the first use of siRNA in human skin. The callus regression seen on the patient's siRNA-treated foot appears sufficiently promising to warrant additional studies of siRNA in this and other dominant-negative skin diseases.
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http://dx.doi.org/10.1038/mt.2009.273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2839285PMC
February 2010
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