Progress towards genetic and pharmacological therapies for keratin genodermatoses: current perspective and future promise.
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.
Department of Dermatology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.
Jean Christopher
JC
Chamcheu
Gary S
GS
Wood
Imtiaz A
IA
Siddiqui
Deeba N
DN
Syed
Vaqar M
VM
Adhami
Joyce M
JM
Teng
Hasan
H
Mukhtar
D000818:Animals; D019274:Botulinum Toxins, Type A / Q000627:therapeutic use; D015316:Genetic Therapy; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D007249:Inflammation / Q000188:drug therapy; D007633:Keratins / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D018832:Molecular Chaperones / Q000378:metabolism; D009154:Mutation; D053758:Nanoparticles / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012176:Retinoids / Q000627:therapeutic use; D012873:Skin Diseases, Genetic / Q000188:drug therapy* / Q000235:genetics*; D025801:Ubiquitin / Q000378:metabolism
D018832:Molecular Chaperones; D012176:Retinoids; D025801:Ubiquitin; D007633:Keratins; D019274:Botulinum Toxins, Type A; D046988:Proteasome Endopeptidase Complex