International Journal of Molecular Sciences

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 1819

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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13 pages, 2100 KiB

Open AccessArticle

COL7A1 Editing via RNA Trans-Splicing in RDEB-Derived Skin Equivalents

by Bernadette Liemberger, Johannes Bischof, Michael Ablinger, Stefan Hainzl, Eva M. Murauer, Nina Lackner, Patricia Ebner, Thomas Kocher, Alexander Nyström, Verena Wally, Elisabeth Mayr, Christina Guttmann-Gruber, Josefina Piñón Hofbauer, Johann W. Bauer and Ulrich Koller

Int. J. Mol. Sci. 2023, 24(5), 4341; https://doi.org/10.3390/ijms24054341 - 22 Feb 2023

Cited by 1 | Viewed by 2172

Abstract

Mutations in the COL7A1 gene lead to malfunction, reduction or complete absence of type VII collagen (C7) in the skin’s basement membrane zone (BMZ), impairing skin integrity. In epidermolysis bullosa (EB), more than 800 mutations in COL7A1 have been reported, leading to the [...] Read more.

Mutations in the COL7A1 gene lead to malfunction, reduction or complete absence of type VII collagen (C7) in the skin’s basement membrane zone (BMZ), impairing skin integrity. In epidermolysis bullosa (EB), more than 800 mutations in COL7A1 have been reported, leading to the dystrophic form of EB (DEB), a severe and rare skin blistering disease associated with a high risk of developing an aggressive form of squamous cell carcinoma. Here, we leveraged a previously described 3′-RTMS6m repair molecule to develop a non-viral, non-invasive and efficient RNA therapy to correct mutations within COL7A1 via spliceosome-mediated RNA trans-splicing (SMaRT). RTM-S6m, cloned into a non-viral minicircle-GFP vector, is capable of correcting all mutations occurring between exon 65 and exon 118 of COL7A1 via SMaRT. Transfection of the RTM into recessive dystrophic EB (RDEB) keratinocytes resulted in a trans-splicing efficiency of ~1.5% in keratinocytes and ~0.6% in fibroblasts, as confirmed on mRNA level via next-generation sequencing (NGS). Full-length C7 protein expression was primarily confirmed in vitro via immunofluorescence (IF) staining and Western blot analysis of transfected cells. Additionally, we complexed 3′-RTMS6m with a DDC642 liposomal carrier to deliver the RTM topically onto RDEB skin equivalents and were subsequently able to detect an accumulation of restored C7 within the basement membrane zone (BMZ). In summary, we transiently corrected COL7A1 mutations in vitro in RDEB keratinocytes and skin equivalents derived from RDEB keratinocytes and fibroblasts using a non-viral 3′-RTMS6m repair molecule. Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Skin Diseases 2.0)

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12 pages, 2538 KiB

Open AccessArticle

Role of Presenilin-1 in Aggressive Human Melanoma

by Julia Sidor, Megan Gillette, Lindsay Ann Dezi, Gustavo Untiveros and Luigi Strizzi

Int. J. Mol. Sci. 2022, 23(9), 4904; https://doi.org/10.3390/ijms23094904 - 28 Apr 2022

Cited by 2 | Viewed by 1751

Abstract

Presenilin-1 (PS-1), a component of the gamma (γ)-secretase catalytic complex, has been implicated in Alzheimer’s disease (AD) and in tumorigenesis. Interestingly, AD risk is inversely related to melanoma, suggesting that AD-related factors, such as PS-1, may affect melanomagenesis. PS-1 has been shown to [...] Read more.

Presenilin-1 (PS-1), a component of the gamma (γ)-secretase catalytic complex, has been implicated in Alzheimer’s disease (AD) and in tumorigenesis. Interestingly, AD risk is inversely related to melanoma, suggesting that AD-related factors, such as PS-1, may affect melanomagenesis. PS-1 has been shown to reduce Wnt activity by promoting degradation of beta-catenin (β-catenin), an important Wnt signaling partner. Since Wnt is known to enhance progression of different cancers, including melanoma, we hypothesized that PS-1 could affect Wnt-associated melanoma aggressiveness. Western blot results showed that aggressive melanoma cells expressed significantly lower levels of both PS-1 and phosphorylated-β-catenin (P-β-catenin) than nonaggressive melanoma cells. Immunohistochemistry of human melanoma samples showed significantly reduced staining for PS-1 in advanced stage melanoma compared with early stage melanoma. Furthermore, γ-secretase inhibitor (GSI) treatment of aggressive melanoma cells was followed by significant increases in PS-1 and P-β-catenin levels, suggesting impaired Wnt signaling activity as PS-1 expression increased. Finally, a significant reduction in cell migration was associated with the higher levels of PS-1 and P-β-catenin in the GSI-treated aggressive melanoma cells. We demonstrate for the first time that PS-1 levels can be used to assess melanoma aggressiveness and suggest that by enhancing PS-1 expression, Wnt-dependent melanoma progression may be reduced Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Skin Diseases 2.0)

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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 - 2 Feb 2022

Cited by 7 | Viewed by 2687

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 [...] Read more.

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 2265

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 [...] Read more.

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 16 | Viewed by 6614

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 [...] Read more.

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 3 | Viewed by 2468

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 [...] Read more.

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 - 5 Jan 2022

Cited by 4 | Viewed by 4698

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), [...] Read more.

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 2284

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 [...] Read more.

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 2977

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 [...] Read more.

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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22 pages, 1586 KiB

Open AccessReview

Challenges of Gene Editing Therapies for Genodermatoses

by Imogen R. Brooks, Adam Sheriff, Declan Moran, Jingbo Wang and Joanna Jacków

Int. J. Mol. Sci. 2023, 24(3), 2298; https://doi.org/10.3390/ijms24032298 - 24 Jan 2023

Cited by 6 | Viewed by 3700

Abstract

Genodermatoses encompass a wide range of inherited skin diseases, many of which are monogenic. Genodermatoses range in severity and result in early-onset cancers or life-threatening damage to the skin, and there are few curative options. As such, there is a clinical need for [...] Read more.

Genodermatoses encompass a wide range of inherited skin diseases, many of which are monogenic. Genodermatoses range in severity and result in early-onset cancers or life-threatening damage to the skin, and there are few curative options. As such, there is a clinical need for single-intervention treatments with curative potential. Here, we discuss the nascent field of gene editing for the treatment of genodermatoses, exploring CRISPR–Cas9 and homology-directed repair, base editing, and prime editing tools for correcting pathogenic mutations. We specifically focus on the optimisation of editing efficiency, the minimisation off-targets edits, and the tools for delivery for potential future therapies. Honing each of these factors is essential for translating gene editing therapies into the clinical setting. Therefore, the aim of this review article is to raise important considerations for investigators aiming to develop gene editing approaches for genodermatoses. Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Skin Diseases 2.0)

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53 pages, 2542 KiB

Open AccessReview

Towards a Better Understanding of Genotype–Phenotype Correlations and Therapeutic Targets for Cardiocutaneous Genes: The Importance of Functional Studies above Prediction

by Mathilde C. S. C. Vermeer, Daniela Andrei, Luisa Marsili, J. Peter van Tintelen, Herman H. W. Silljé, Maarten P. van den Berg, Peter van der Meer and Maria C. Bolling

Int. J. Mol. Sci. 2022, 23(18), 10765; https://doi.org/10.3390/ijms231810765 - 15 Sep 2022

Cited by 5 | Viewed by 1858

Abstract

Genetic variants in gene-encoding proteins involved in cell–cell connecting structures, such as desmosomes and gap junctions, may cause a skin and/or cardiac phenotype, of which the combination is called cardiocutaneous syndrome. The cardiac phenotype is characterized by cardiomyopathy and/or arrhythmias, while the skin [...] Read more.

Genetic variants in gene-encoding proteins involved in cell–cell connecting structures, such as desmosomes and gap junctions, may cause a skin and/or cardiac phenotype, of which the combination is called cardiocutaneous syndrome. The cardiac phenotype is characterized by cardiomyopathy and/or arrhythmias, while the skin particularly displays phenotypes such as keratoderma, hair abnormalities and skin fragility. The reported variants associated with cardiocutaneous syndrome, in genes DSP, JUP, DSC2, KLHL24, GJA1, are classified by interpretation guidelines from the American College of Medical Genetics and Genomics. The genotype–phenotype correlation, however, remains poorly understood. By providing an overview of variants that are assessed for a functional protein pathology, we show that this number (n = 115) is low compared to the number of variants that are assessed by in silico algorithms (>5000). As expected, there is a mismatch between the prediction of variant pathogenicity and the prediction of the functional effect compared to the real functional evidence. Aiding to improve genotype–phenotype correlations, we separate variants into ‘protein reducing’ or ‘altered protein’ variants and provide general conclusions about the skin and heart phenotype involved. We conclude by stipulating that adequate prognoses can only be given, and targeted therapies can only be designed, upon full knowledge of the protein pathology through functional investigation. Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Skin Diseases 2.0)

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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 2666

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 [...] Read more.

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 2472

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 [...] Read more.

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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13 pages, 3000 KiB

Open AccessCase Report

EBS in Children with De Novo Pathogenic Variants Disturbing Krt14

by Anastasiya V. Kosykh, Irina I. Ryumina, Alexandra S. Botkina, Nadezhda A. Evtushenko, Elena B. Zhigmitova, Aleksandra A. Martynova, Nadya G. Gurskaya and Denis V. Rebrikov

Int. J. Mol. Sci. 2024, 25(5), 2989; https://doi.org/10.3390/ijms25052989 - 4 Mar 2024

Viewed by 553

Abstract

Epidermolysis bullosa simplex (EBS) is a dermatological condition marked by skin fragility and blister formation resulting from separation within the basal layer of the epidermis, which can be attributed to various genetic etiologies. This study presents three pathogenic de novo variants in young [...] Read more.

Epidermolysis bullosa simplex (EBS) is a dermatological condition marked by skin fragility and blister formation resulting from separation within the basal layer of the epidermis, which can be attributed to various genetic etiologies. This study presents three pathogenic de novo variants in young children, with clinical manifestations appearing as early as the neonatal period. The variants contribute to the EBS phenotype through two distinct mechanisms: direct keratin abnormalities due to pathogenic variants in the Krt14 gene, and indirect effects via pathogenic mutation in the KLHL24 gene, which interfere with the natural proteasome-mediated degradation pathway of KRT14. We report one severe case of EBS with mottled pigmentation arising from the Met119Thr pathogenic variant in KRT14, another case involving a pathogenic KLHL24 Met1Val variant, and a third case featuring the hot spot mutation Arg125His in KRT14, all manifesting within the first few weeks of life. This research underscores the complexity of genetic influences in EBS and highlights the importance of early genetic screening for accurate diagnosis and management. Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Skin Diseases 2.0)

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