Progress towards genetic and pharmacological therapies for keratin genodermatoses: current perspective and future promise

Abstract

Hereditary keratin disorders of the skin and its appendages comprise a large group of clinically heterogeneous disfiguring blistering and ichthyotic diseases, primarily characterized by the loss of tissue integrity, blistering and hyperkeratosis in severely affected tissues. Pathogenic mutations in keratins cause these afflictions. Typically, these mutations in concert with characteristic features have formed the basis for improved disease diagnosis, prognosis and most recently therapy development. Examples include epidermolysis bullosa simplex, keratinopathic ichthyosis, pachyonychia congenita and several other tissue-specific hereditary keratinopathies. Understanding the molecular and genetic events underlying skin dysfunction has initiated alternative treatment approaches that may provide novel therapeutic opportunities for affected patients. Animal and in vitro disease modelling studies have shed more light on molecular pathogenesis, further defining the role of keratins in disease processes and promoting the translational development of new gene and pharmacological therapeutic strategies. Given that the molecular basis for these monogenic disorders is well established, gene therapy and drug discovery targeting pharmacological compounds with the ability to reinforce the compromised cytoskeleton may lead to promising new therapeutic strategies for treating hereditary keratinopathies. In this review, we will summarize and discuss recent advances in the preclinical and clinical modelling and development of gene, natural product, pharmacological and protein-based therapies for these disorders, highlighting the feasibility of new approaches for translational clinical therapy.

Imbalance of intermediate filament component keratin 14 contributes to increased stress signalling in epidermolysis bullosa simplex

“…These data should help broaden the still narrow field of therapeutic approaches to EBS (17) and raise awareness to the possibility that as a secondary effect of the K14 mutation, imbalance of IF components and the associated amplification of MAPK signalling could play an important role in the pathophysiology of the disease.…”

Keratins and skin disease

“…These focus on (1) modulating the inflammatory response, (2) gene modifiers, (3) molecular chaperones, ubiquitin-proteasome and MAP kinase signalling systems and (4) compensatory molecules for supplementation therapy (Chamcheu et al 2012).…”

Modern concepts of pathogenesis of ichthyosis

“…На наш погляд, це зумовлено недостатньо розробленою концепцією па-тогенезу даного захворювання, що гальмує розробку концептуально нових засобів впливу. Багатьма дослід-никами підкреслюється, що не існує стандартизованих підходів до лікування іхтіозу [4], також вказується, що удосконалення знань про патогенез іхтіозу має суттєвий вплив на результативність терапії захворювання [5]. На сьогодні існують численні дослідження присвячені виявленню генетичних мутацій [6][7][8][9][10], які є специфіч-ними для іхтіозу, однак залишається неясним механізм реалізації їх на молекулярно-клітинному рівні.…”