Gene Therapy for Inherited Skin Disorders

Abstract

Inherited skin disorders are caused by pathogenic mutations in over 500 genes. These mutations result in a spectrum of cutaneous and systemic abnormalities that generate considerable morbidity, and occasionally mortality. To date, however, there are no effective treatments. Nevertheless, the easy accessibility of skin, together with advances in molecular genetics and biotechnology, has paved the way for gene therapy development and testing. Gene therapy aims to reverse the pathology and phenotype of a particular disease through supplementation of the defective gene with a single normal full‐length copy or correction of the underlying mutant gene via genome editing or RNA (ribonucleic acid)‐based methods.

Key Concepts

  • Inherited skin disorders (also known as genodermatoses) encompass a group of genetic skin diseases in which single‐ or multiple‐gene defects account for a wide spectrum of clinical phenotypes with significant physical and psychosocial impact.
  • Epidermolysis bullosa (EB) is a diverse group of autosomal dominant and recessive blistering skin diseases that affects ∼500 000 people worldwide. In EB, relatively minor trauma to the skin causes blistering which can be complicated by delayed healing and scarring. There is a desperate clinical need for effective therapies, including gene therapy.
  • Gene therapy involves manipulation of cellular DNA or RNA to provide therapeutic benefit using various strategies. These include gene modification through gene addition or replacement, and gene correction through RNA‐based technologies or genome editing tools. Single‐gene disorders are therefore good candidates for gene therapy.
  • The choice of gene therapy strategy in genodermatoses depends on the mode of inheritance and the nature of the pathogenic mutations of a particular disorder.
  • Given that most autosomal recessive skin disorders result in loss of function, deficiency or absence of the wild‐type protein, restoring protein function through the addition of a wild‐type copy of the mutant gene, or correction of the mutant gene, is an appropriate therapeutic goal.
  • In contrast, heterozygous mutations in dominant skin disorders typically result in dominant‐negative interference of the mutant/wild‐type proteins. Thus, therapeutic benefits are best sought by knockdown/silencing of the mutant allele while preserving the functional wild‐type allele, through applying gene correction techniques using small interfering RNA (siRNA) or gene editing endonucleases.

Keywords: skin; genodermatoses; epidermolysis bullosa; gene therapy; gene addition; gene correction; gene editing; vector; lentivirus; retrovirus

Figure 1. The clinical challenge of gene therapy for inherited skin diseases. Effective strategies must take into account the nature of the skin pathology which influences how gene therapy should be designed and delivered for clinical benefits. (a) Blistering skin in recessive dystrophic epidermolysis bullosa (COL7A1); (b) macerated palmar keratoderma in keratitis‐ichthyosis‐deafness syndrome (GJB2); (c) destructive nail changes in Schopf–Schulz–Passarge syndrome (WNT10A); (d) erosive scalp dermatitis in ankyloblepharon‐ectodermal defects‐clefting syndrome (TP63); (e) abnormal hair in woolly hair syndrome (DSP); (f) keratoderma involving the heels (KRT1); (g) epidermolytic ichthyosis on the trunk (KRT10); (h) skin atrophy in Kindler syndrome (KIND1/FERMT1); (i) palmar keratoderma (DSG1); (j) mucosal erosions and gingivitis in Kindler syndrome; (k) mucosal thickening in lipoid proteinosis (ECM1).
Figure 2. Illustration of viral vector‐mediated ex vivo autologous gene therapy.
Figure 3. The molecular basis of inherited skin fragility (epidermolysis bullosa, EB). The top figure shows the light microscopic appearances of normal skin. The bottom figure is a schematic of the lower part of the epidermis highlighting the various structural proteins that may be mutated in various forms of EB. Pathogenic mutations usually result in impaired synthesis or function of a specific protein leading to trauma‐induced blistering wherever that protein is expressed in the skin.
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Further Reading

Abdul‐Wahab A, Qasim W and McGrath JA (2014) Gene therapies for inherited skin disorders. Seminars in Cutaneous Medicine and Surgery 33 (2): 83–90.

Berger A, Maire S, Gaillard M‐C, et al. (2016) mRNA trans‐splicing in gene therapy for genetic diseases. Wiley Interdisciplinary Reviews: RNA 7 (4): 487–498.

Carretero M, Escamez MJ, Prada F, et al. (2006) Skin gene therapy for acquired and inherited disorders. Histology and Histopathology 21 (11): 1233–1247.

Chamcheu JC, Wood GS, Siddiqui IA, et al. (2012) Progress towards genetic and pharmacological therapies for keratin genodermatoses: current perspective and future promise. Experimental Dermatology 21 (7): 481–489.

Hengge UR and Bardenheuer W (2004) Gene therapy and the skin. American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 131C: 93–100.

Petrova A, Ilic D and McGrath JA (2010) Stem cell therapies for recessive dystrophic epidermolysis bullosa. British Journal of Dermatology 163 (6): 1149–1156.

Tolarova M, McGrath JA and Tolar J (2016) Venturing into the new science of nucleases. Journal of Investigative Dermatology 136 (4): 742–745.

Uitto J, Christiano AM, McLean WHI and McGrath JA (2012) Novel molecular therapies for heritable skin disorders. Journal of Investigative Dermatology 132 (3 Pt 2): 820–828.

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Lwin, Su M, and McGrath, John A(Apr 2017) Gene Therapy for Inherited Skin Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026940]