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Molecular Research and Treatment of Skin Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 October 2021) | Viewed by 31330

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Prof. Dr. Johann Bauer

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EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University Salzburg, 5020 Salzburg, Austria
Interests: genodermatoses; epidermolysis bullosa; skin diseases; gene therapy; cDNA replacement; gene editing; CRISPR/Cas9; RNA therapy; small molecules
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Dr. Ulrich Koller

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EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University Salzburg, 5020 Salzburg, Austria
Interests: genodermatoses; epidermolysis bullosa; skin diseases, gene therapy; cDNA replacement, gene editing; CRISPR/Cas9; RNA therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Genodermatoses comprise a group of monogenetic skin disorders with considerable clinical heterogeneity. Clinical manifestations include skin blistering and scaring, mucosal involvement, inherited tumorigenesis, and increased photosensitivity and dermal vulnerability. Therapeutic targets comprise epidermal/dermal genes such as keratins, filaggrin, laminins, collagens, integrins, or components of the DNA repair pathway. The high diversity of associated genes and disease-causing mutations results in a variety of phenotypic severities and clinical outcomes. Therefore, developing treatments that target disease-associated complications along with causal therapies remains the focus of current research attempts in order to increase patient’s quality of life. In this dedicated issue, we therefore welcome both basic and translational research, as well as review articles dealing with causal to symptom relieving approaches, which include gene, RNA, and cell therapies, as well as drug developments based on small molecules.

Prof. Dr. Johann Bauer
Dr. Ulrich Koller
Guest Editors

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Keywords

genodermatoses
skin diseases
gene therapy
cDNA replacement
gene editing
CRISPR/Cas9
RNA therapy
small molecules

Related Special Issue

Molecular Research and Treatment of Skin Diseases 2.0 in International Journal of Molecular Sciences (15 articles)

Published Papers (10 papers)

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Editorial

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4 pages, 190 KiB

Open AccessEditorial

Molecular Research and Treatment of Skin Diseases

by Ulrich Koller and Johann W. Bauer

Int. J. Mol. Sci. 2022, 23(10), 5435; https://doi.org/10.3390/ijms23105435 - 13 May 2022

Cited by 1 | Viewed by 1764

Abstract

The intention of this Special Issue is to highlight current treatment options to target the cause, as well as disease-associated complications, of skin diseases, including a group of monogenetic skin disorders referred to as genodermatoses [...] Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Skin Diseases)

Research

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14 pages, 1446 KiB

Open AccessArticle

5′RNA Trans-Splicing Repair of COL7A1 Mutant Transcripts in Epidermolysis Bullosa

by Elisabeth Mayr, Michael Ablinger, Thomas Lettner, Eva M. Murauer, Christina Guttmann-Gruber, Josefina Piñón Hofbauer, Stefan Hainzl, Manfred Kaiser, Alfred Klausegger, Johann W. Bauer, Ulrich Koller and Verena Wally

Int. J. Mol. Sci. 2022, 23(3), 1732; https://doi.org/10.3390/ijms23031732 - 02 Feb 2022

Cited by 7 | Viewed by 2628

Abstract

Mutations within the COL7A1 gene underlie the inherited recessive subtype of the blistering skin disease dystrophic epidermolysis bullosa (RDEB). Although gene replacement approaches for genodermatoses are clinically advanced, their implementation for RDEB is challenging and requires endogenous regulation of transgene expression. Thus, we are using spliceosome-mediated RNA trans-splicing (SMaRT) to repair mutations in COL7A1 at the mRNA level. Here, we demonstrate the capability of a COL7A1-specific RNA trans-splicing molecule (RTM), initially selected using a fluorescence-based screening procedure, to accurately replace COL7A1 exons 1 to 64 in an endogenous setting. Retroviral RTM transduction into patient-derived, immortalized keratinocytes resulted in an increase in wild-type transcript and protein levels, respectively. Furthermore, we revealed accurate deposition of recovered type VII collagen protein within the basement membrane zone of expanded skin equivalents using immunofluorescence staining. In summary, we showed for the first time the potential of endogenous 5′ trans-splicing to correct pathogenic mutations within the COL7A1 gene. Therefore, we consider 5′ RNA trans-splicing a suitable tool to beneficially modulate the RDEB-phenotype, thus targeting an urgent need of this patient population. Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Skin Diseases)

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17 pages, 2462 KiB

Open AccessArticle

Paclitaxel-Induced Epidermal Alterations: An In Vitro Preclinical Assessment in Primary Keratinocytes and in a 3D Epidermis Model

by Paula Montero, Javier Milara, Martín Pérez-Leal, Cristina Estornut, Inés Roger, Alejandro Pérez-Fidalgo, Celia Sanz and Julio Cortijo

Int. J. Mol. Sci. 2022, 23(3), 1142; https://doi.org/10.3390/ijms23031142 - 20 Jan 2022

Cited by 7 | Viewed by 2200

Abstract

Paclitaxel is a microtubule-stabilizing chemotherapeutic agent approved for the treatment of ovarian, non-small cell lung, head, neck, and breast cancers. Despite its beneficial effects on cancer and widespread use, paclitaxel also damages healthy tissues, including the skin. However, the mechanisms that drive these skin adverse events are not clearly understood. In the present study, we demonstrated, by using both primary epidermal keratinocytes (NHEK) and a 3D epidermis model, that paclitaxel impairs different cellular processes: paclitaxel increased the release of IL-1α, IL-6, and IL-8 inflammatory cytokines, produced reactive oxygen species (ROS) release and apoptosis, and reduced the endothelial tube formation in the dermal microvascular endothelial cells (HDMEC). Some of the mechanisms driving these adverse skin events in vitro are mediated by the activation of toll-like receptor 4 (TLR-4), which phosphorylate transcription of nuclear factor kappa B (NF-κb). This is the first study analyzing paclitaxel effects on healthy human epidermal cells with an epidermis 3D model, and will help in understanding paclitaxel’s effects on the skin. Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Skin Diseases)

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16 pages, 4796 KiB

Open AccessArticle

Effect of a Topical Collagen Tripeptide on Antiaging and Inhibition of Glycation of the Skin: A Pilot Study

by Young In Lee, Sang Gyu Lee, Inhee Jung, Jangmi Suk, Mun-Hoe Lee, Do-Un Kim and Ju Hee Lee

Int. J. Mol. Sci. 2022, 23(3), 1101; https://doi.org/10.3390/ijms23031101 - 20 Jan 2022

Cited by 15 | Viewed by 6399

Abstract

The glycation process has been recognized as one of the critical parameters that accelerate signs of skin aging, especially in skin exposed to environment factors, such as ultraviolet radiation. Although previous studies showed the anti-inflammatory and antiaging properties of the hydrolyzed collagen tripeptide (CTP), its exact mechanism is not fully understood. Therefore, in this study, we sought to investigate the effect of a topical CTP on facial skin. Our group designed a 4 week prospective, single-arm study of 22 Asian women who applied topical CTP. We observed significant improvements in skin wrinkles, elasticity, and density with a reduction in skin accumulation of advanced glycated end products (AGEs) at week 4 without any adverse effects. The in vitro study revealed a preventive effect of the topical CTP on the accumulation of AGEs, denatured collagen production, and reactive oxygen species in dermal fibroblasts. Moreover, treatment with the CTP decreased induction of matrix metalloproteinases while increasing the collagen 1 level. These results suggest that the application of a topical CTP might improve clinical aging phenotypes via the inhibition of glycation and oxidative stress, leading to a delay in cellular aging. Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Skin Diseases)

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12 pages, 1797 KiB

Open AccessArticle

Transcriptome-Guided Drug Repurposing for Aggressive SCCs

by Roland Zauner, Monika Wimmer, Sonja Dorfer, Michael Ablinger, Ulrich Koller, Josefina Piñón Hofbauer, Christina Guttmann-Gruber, Johann W. Bauer and Verena Wally

Int. J. Mol. Sci. 2022, 23(2), 1007; https://doi.org/10.3390/ijms23021007 - 17 Jan 2022

Cited by 2 | Viewed by 2411

Abstract

Despite a significant rise in the incidence of cutaneous squamous cell carcinoma (SCC) in recent years, most SCCs are well treatable. However, against the background of pre-existing risk factors such as immunosuppression upon organ transplantation, or conditions such as recessive dystrophic epidermolysis bullosa (RDEB), SCCs arise more frequently and follow a particularly aggressive course. Notably, such SCC types display molecular similarities, despite their differing etiologies. We leveraged the similarities in transcriptomes between tumors from organ transplant recipients and RDEB-patients, augmented with data from more common head and neck (HN)-SCCs, to identify drugs that can be repurposed to treat these SCCs. The in silico approach used is based on the assumption that SCC-derived transcriptome profiles reflect critical tumor pathways that, if reversed towards healthy tissue, will attenuate the malignant phenotype. We determined tumor-specific signatures based on differentially expressed genes, which were then used to mine drug-perturbation data. By leveraging recent efforts in the systematic profiling and cataloguing of thousands of small molecule compounds, we identified drugs including selumetinib that specifically target key molecules within the MEK signaling cascade, representing candidates with the potential to be effective in the treatment of these rare and aggressive SCCs. Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Skin Diseases)

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13 pages, 2337 KiB

Open AccessArticle

Evaluating a Targeted Cancer Therapy Approach Mediated by RNA trans-Splicing In Vitro and in a Xenograft Model for Epidermolysis Bullosa-Associated Skin Cancer

by Katharina Woess, Yuchen Sun, Hanae Morio, Anna Stierschneider, Anna Kaufmann, Stefan Hainzl, Lisa Trattner, Thomas Kocher, Birgit Tockner, Victoria Leb-Reichl, Markus Steiner, Gabriele Brachtl, Andrew P. South, Johann W. Bauer, Julia Reichelt, Tomomi Furihata, Verena Wally, Ulrich Koller, Josefina Piñón Hofbauer and Christina Guttmann-Gruber

Int. J. Mol. Sci. 2022, 23(1), 575; https://doi.org/10.3390/ijms23010575 - 05 Jan 2022

Cited by 4 | Viewed by 4622

Abstract

Conventional anti-cancer therapies based on chemo- and/or radiotherapy represent highly effective means to kill cancer cells but lack tumor specificity and, therefore, result in a wide range of iatrogenic effects. A promising approach to overcome this obstacle is spliceosome-mediated RNA trans-splicing (SMaRT), which can be leveraged to target tumor cells while leaving normal cells unharmed. Notably, a previously established RNA trans-splicing molecule (RTM44) showed efficacy and specificity in exchanging the coding sequence of a cancer target gene (Ct-SLCO1B3) with the suicide gene HSV1-thymidine kinase in a colorectal cancer model, thereby rendering tumor cells sensitive to the prodrug ganciclovir (GCV). In the present work, we expand the application of this approach, using the same RTM44 in aggressive skin cancer arising in the rare genetic skin disease recessive dystrophic epidermolysis bullosa (RDEB). Stable expression of RTM44, but not a splicing-deficient control (NC), in RDEB-SCC cells resulted in expression of the expected fusion product at the mRNA and protein level. Importantly, systemic GCV treatment of mice bearing RTM44-expressing cancer cells resulted in a significant reduction in tumor volume and weight compared with controls. Thus, our results demonstrate the applicability of RTM44-mediated targeting of the cancer gene Ct-SLCO1B3 in a different malignancy. Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Skin Diseases)

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11 pages, 2748 KiB

Open AccessArticle

Janus Kinase Inhibitors Ameliorated Gastrointestinal Amyloidosis and Hypoalbuminemia in Persistent Dermatitis Mouse Model

by Takehisa Nakanishi, Kento Mizutani, Shohei Iida, Yoshiaki Matsushima, Ai Umaoka, Makoto Kondo, Koji Habe and Keiichi Yamanaka

Int. J. Mol. Sci. 2022, 23(1), 28; https://doi.org/10.3390/ijms23010028 - 21 Dec 2021

Cited by 11 | Viewed by 2225

Abstract

Malnutrition is not only regarded as a complication of rheumatoid arthritis and inflammatory bowel disease but also that of inflammatory skin disease; however, the mechanisms and efficacy of its treatment have not been elucidated. Using a mouse model of dermatitis, we investigated the pathophysiology of malnutrition in inflammatory skin conditions and efficacy of its treatment. We employed spontaneous skin inflammation mice models overexpressing human caspase-1 in the epidermal keratinocytes. Body weight, nutrition level, and α1-antitrypsin fecal concentration were measured. The gastrointestinal tract was histologically and functionally investigated. Fluorescein isothiocyanate (FITC)-dextran was forcibly fed on an empty stomach, and plasma FITC-dextran was measured. The treatment efficacy of antibodies against tumor necrosis factor-α (TNF-α) and interleukin (IL)-α/β as well as Janus kinase (JAK) inhibitors was investigated. Compared with wild-type littermates, the inflammatory skin mice models showed a lowered body weight, reduction of serum albumin level, amyloid deposition in the stomach, small intestine, and large intestine, and increased α1-antitrypsin fecal concentration. However, the plasma FITC-dextran was unchanged between the dermatitis models and wild-type littermates. The over-produced serum amyloid A1 in the liver was detected in the plasma in the dermatitis model. Antibodies against TNF-α and IL-α/β showed partial effects on amyloid deposition; however, JAK inhibitors improved gastrointestinal amyloidosis with the improvement of skin symptoms. Chronic dermatitis is closely related to secondary amyloidosis in the gastrointestinal tract, resulting in hypoalbuminemia. Therefore, active control of skin inflammation is essential for preventing gastrointestinal complications. Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Skin Diseases)

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15 pages, 2572 KiB

Open AccessArticle

Development of Minicircle Vectors Encoding COL7A1 Gene with Human Promoters for Non-Viral Gene Therapy for Recessive Dystrophic Epidermolysis Bullosa

by Xianqing Wang, Fatma Alshehri, Darío Manzanares, Yinghao Li, Zhonglei He, Bei Qiu, Ming Zeng, Sigen A, Irene Lara-Sáez and Wenxin Wang

Int. J. Mol. Sci. 2021, 22(23), 12774; https://doi.org/10.3390/ijms222312774 - 26 Nov 2021

Cited by 8 | Viewed by 2911

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare autosomal inherited skin disorder caused by mutations in the COL7A1 gene that encodes type VII collagen (C7). The development of an efficient gene replacement strategy for RDEB is mainly hindered by the lack of vectors able to encapsulate and transfect the large cDNA size of this gene. To address this problem, our group has opted to use polymeric-based non-viral delivery systems and minicircle DNA. With this approach, safety is improved by avoiding the usage of viruses, the absence of bacterial backbone, and the replacement of the control viral cytomegalovirus (CMV) promoter of the gene with human promoters. All the promoters showed impressive C7 expression in RDEB skin cells, with eukaryotic translation elongation factor 1 α (EF1α) promoter producing higher C7 expression levels than CMV following minicircle induction, and COL7A1 tissue-specific promoter (C7P) generating C7 levels similar to normal human epidermal keratinocytes. The improved system developed here has a high potential for use as a non-viral topical treatment to restore C7 in RDEB patients efficiently and safely, and to be adapted to other genetic conditions. Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Skin Diseases)

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Review

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10 pages, 439 KiB

Open AccessReview

Epigenetics of Cutaneous T-Cell Lymphomas

by Natsumi Hara and Yu Sawada

Int. J. Mol. Sci. 2022, 23(7), 3538; https://doi.org/10.3390/ijms23073538 - 24 Mar 2022

Cited by 3 | Viewed by 2558

Abstract

Epigenetic modifications rarely occur in isolation (as single “epigenetic modifications”). They usually appear together and form a network to control the epigenetic system. Cutaneous malignancies are usually affected by epigenetic changes. However, there is limited knowledge regarding the epigenetic changes associated with cutaneous lymphomas. In this review, we focused on cutaneous T-cell lymphomas such as mycosis fungoides, Sézary syndrome, and anaplastic large cell lymphoma. With regard to epigenetic changes, we summarize the detailed chemical modifications categorized into DNA methylation and histone acetylation and methylation. We also summarize the epigenetic modifications and characteristics of the drug for cutaneous T-cell lymphoma (CTCL). Furthermore, we discuss current research on epigenetic-targeted therapy against cutaneous T-cell lymphomas. Although the current method of treatment with histone deacetylase inhibitors does not exhibit sufficient therapeutic benefits in all cases of CTCL, epigenetic-targeted combination therapy might overcome this limitation for patients with CTCL. Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Skin Diseases)

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15 pages, 2604 KiB

Open AccessReview

Therapeutic Prospects of Exon Skipping for Epidermolysis Bullosa

by Franciscus C. Vermeer, Jeroen Bremer, Robert J. Sietsma, Aileen Sandilands, Robyn P. Hickerson, Marieke C. Bolling, Anna M.G. Pasmooij, Henny H. Lemmink, Morris A. Swertz, Nine V.A.M. Knoers, K. Joeri van der Velde and Peter C. van den Akker

Int. J. Mol. Sci. 2021, 22(22), 12222; https://doi.org/10.3390/ijms222212222 - 12 Nov 2021

Cited by 7 | Viewed by 2413

Abstract

Epidermolysis bullosa is a group of genetic skin conditions characterized by abnormal skin (and mucosal) fragility caused by pathogenic variants in various genes. The disease severity ranges from early childhood mortality in the most severe types to occasional acral blistering in the mildest types. The subtype and severity of EB is linked to the gene involved and the specific variants in that gene, which also determine its mode of inheritance. Current treatment is mainly focused on symptomatic relief such as wound care and blister prevention, because truly curative treatment options are still at the preclinical stage. Given the current level of understanding, the broad spectrum of genes and variants underlying EB makes it impossible to develop a single treatment strategy for all patients. It is likely that many different variant-specific treatment strategies will be needed to ultimately treat all patients. Antisense-oligonucleotide (ASO)-mediated exon skipping aims to counteract pathogenic sequence variants by restoring the open reading frame through the removal of the mutant exon from the pre-messenger RNA. This should lead to the restored production of the protein absent in the affected skin and, consequently, improvement of the phenotype. Several preclinical studies have demonstrated that exon skipping can restore protein production in vitro, in skin equivalents, and in skin grafts derived from EB-patient skin cells, indicating that ASO-mediated exon skipping could be a viable strategy as a topical or systemic treatment. The potential value of exon skipping for EB is supported by a study showing reduced phenotypic severity in patients who carry variants that result in natural exon skipping. In this article, we review the substantial progress made on exon skipping for EB in the past 15 years and highlight the opportunities and current challenges of this RNA-based therapy approach. In addition, we present a prioritization strategy for the development of exon skipping based on genomic information of all EB-involved genes. Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Skin Diseases)

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