Exposed CendR Domain in Homing Peptide Yields Skin-Targeted Therapeutic in Epidermolysis Bullosa.

Systemic skin-selective therapeutics would be a major advancement in the treatment of diseases affecting the entire skin, such as recessive dystrophic epidermolysis bullosa (RDEB), which is caused by mutations in the COL7A1 gene and manifests in transforming growth factor-ß (TGF-ß)-driven fibrosis and malignant transformation. Homing peptides containing a C-terminal R/KXXR/K motif (C-end rule [CendR] sequence) activate an extravasation and tissue penetration pathway for tumor-specific drug delivery. We have previously described a homing peptide CRKDKC (CRK) that contains a cryptic CendR motif and homes to angiogenic blood vessels in wounds and tumors, but it cannot penetrate cells or tissues. In this study, we demonstrate that removal of the cysteine from CRK to expose the CendR sequence confers the peptide novel ability to home to normal skin. Fusion of the truncated CRK (tCRK) peptide to the C terminus of an extracellular matrix protein decorin (DCN), a natural TGF-ß inhibitor, resulted in a skin-homing therapeutic molecule (DCN-tCRK). Systemic DCN-tCRK administration in RDEB mice led to inhibition of TGF-ß signaling in the skin and significant improvement in the survival of RDEB mice. These results suggest that DCN-tCRK has the potential to be utilized as a novel therapeutic compound for the treatment of dermatological diseases such as RDEB.

Molecular Therapeutics in Development for Epidermolysis Bullosa: Update 2020.

Epidermolysis bullosa (EB) is a group of rare genetic disorders for which significant progress has been achieved in the development of molecular therapies in the last few decades. Such therapies require knowledge of mutant genes and specific mutations, some of them being allele specific. A relatively large number of clinical trials are ongoing and ascertaining the clinical efficacy of gene, protein or cell therapies or of repurposed drugs, mainly in recessive dystrophic EB. It is expected that some new drugs may emerge in the near future and that combinations of different approaches may result in improved treatment outcomes for individuals with EB.

A nutrition-based approach to epidermolysis bullosa: Causes, assessments, requirements and management.

Inherited epidermolysis bullosa (EB) is a clinically and genetically heterogeneous group of rare diseases characterized by skin and mucous membrane fragility. EB primarily involves the skin and, in specific subtypes, the mucous membrane, resulting in complications which can strongly affect nutritional status (e.g. gastrointestinal complications, hand deformities, pain). The aims of nutritional support mainly include improving nutritional status, alleviating the stress of oral feeding and minimizing nutritional deficiencies, thus consequently improving growth, pubertal development, bowel function, immune status and wound healing. The aim of this review is to discuss knowledge of different aspects of the disease related to nutrition and growth.

Dermal regeneration template: a new option for the repair of a large surgical defect after mohs surgery in epidermolysis bullosa

La epidermólisis ampollar es un raro trastorno hereditario caracterizado por fragilidad cutánea, formación de ampollas mucocutáneas recurrentes luego de un traumatismo mínimo y cicatrización deficiente de heridas. Además, algunas variantes se han asociado con la aparición de carcinomas espinocelulares. Presentamos el caso clínico de un paciente con epidermólisis ampollar, que presentó un extenso carcinoma espinocelular localizado en cara posterior de brazo. Este fue tratado con cirugía micrográfica de Mohs y el defecto quirúrgico resultante fue reparado aplicando una matriz de regeneración dérmica sobre la herida durante un mes. Posteriormente continuamos con curaciones y ungüento antibiótico sobre la herida dos veces al día, completando la cicatrización con un excelente resultado cosmético y funcional. Enfatizamos en el carácter novedoso de esta opción terapéutica y en su utilidad en pacientes con epidermólisis ampollar.

Epidermolysis bullosa is a rare hereditary disorder characterized by skin fragility, recurrent mucocutaneous blisters following minimal trauma, and compromised wound healing. Moreover, some variants have been associated with squamous cell carcinoma. Following, we present the clinical case of a patient with epidermolysis bullosa, who presented a large squamous cell carcinoma of the arm. It was resected using Mohs micrographic surgery, and the final defect was repaired by applying a dermal regeneration template over the wound for a month. After this period, we continued using cures and antibiotic ointment over the wound twice a day, and healing was completed with excellent cosmetic and functional results. We emphasize the novelty of this therapeutic option, and its usefulness in patients with epidermolysis bullosa.

Treatment of keratinocytes with 4-phenylbutyrate in epidermolysis bullosa: Lessons for therapies in keratin disorders.

BACKGROUND: Missense mutations in keratin 5 and 14 genes cause the severe skin fragility disorder epidermolysis bullosa simplex (EBS) by collapsing of the keratin cytoskeleton into cytoplasmic protein aggregates. Despite intense efforts, no molecular therapies are available, mostly due to the complex phenotype of EBS, comprising cell fragility, diminished adhesion, skin inflammation and itch. METHODS: We extensively characterized KRT5 and KRT14 mutant keratinocytes from patients with severe generalized EBS following exposure to the chemical chaperone 4-phenylbutyrate (4-PBA). FINDINGS: 4-PBA diminished keratin aggregates within EBS cells and ameliorated their inflammatory phenotype. Chemoproteomics of 4-PBA-treated and untreated EBS cells revealed reduced IL1ß expression- but also showed activation of Wnt/ß-catenin and NF-kB pathways. The abundance of extracellular matrix and cytoskeletal proteins was significantly altered, coinciding with diminished keratinocyte adhesion and migration in a 4-PBA dose-dependent manner. INTERPRETATION: Together, our study reveals a complex interplay of benefits and disadvantages that challenge the use of 4-PBA in skin fragility disorders.

Epidermolysis bullosa and the partnership with autoimmunity: what should we assimilate?

Bullous skin diseases are characterized by genetic abnormalities related to structural epidermal proteins or organ-specific autoantibodies against the same proteins and are revealed by blister formation on skin or mucous membranes, with differences in blister depth, morphology, and topography. Both inherited and autoimmune forms of these disorders can be framed in the context of epidermolysis bullosa. Their clinical spectrum varies from early lethal to mild variants with normal life expectancy, and several distinct phenotypes differ for age of onset, extent, location and depth of skin and mucous lesions, or scarring severity. Recently, different inflammatory processes blended with autoimmune phenomena have been demonstrated in both inherited and acquired epidermolysis bullosa, revealing that this overlapping might cause substantial implications in terms of disease course and outcome. Although several associations between epidermolysis bullosa in its different variants and autoimmune diseases have been reported, it is not yet completely clear how it happens and why this association occurs in only some patients. Autoantibodies are the primary cause of the disease in acquired epidermolysis bullosa, whereas they can be produced as a secondary event due to genetically determined skin damage in inherited epidermolysis bullosa, contributing significantly to the worsening of the disease. The awareness of this overlap may help in identifying new therapeutic approaches with immunosuppressive drugs that could have a significant impact in terms of prognosis.

Epidermolysis bullosa pruriginosa triggered by scabies infestation.

Epidermolysis bullosa pruriginosa (EB-Pr) is an unusual variant of dystrophic EB. Potential genetic disease modifiers and metabolic factors have been investigated, but thus far no specific insight into this phenotype has emerged. We report an in-depth description of three patients diagnosed as having EB-Pr in whom this particular phenotype developed after scabies infestation and dramatically improved after full treatment. This short communication suggests that scabies infestation could be one of the important triggering factors for the development of the EB-Pr phenotype.

Nutrition and bullous skin diseases.

Autoimmune and nonautoimmune bullous diseases can both be associated with significant morbidity and mortality. Although our understanding of the pathogenic mechanisms of these diseases has increased tremendously, there is still much to learn about the various factors affecting their onset, course, and therapy. In recent years, increasing information has been published about the effect of vitamins, minerals, and other nutrients on bullous skin diseases. Some factors are believed to be inducers (thiol and phenol-containing foods in pemphigus), whereas others are believed to be protective (antioxidants in cutaneous porphyrias). This contribution reviews the evidence in the literature of the role of various dietary factors in bullous diseases, including the nonautoimmune and the deficiency dermatoses. Additional studies and new investigations are needed to provide a better understanding of the specific associations of dietary factors with bullous diseases and better management for patients affected by these conditions.

Laserterapia na epidermólise bolhosa: revisão daliteratura e relato de caso / Lasertherapy in epidermolysis bullosa: review of literature and case report

Os autores apresentam um caso clínico de Epidermólise Bolhosa (EB), atendido na clínica da disciplinade Odontologia para Pacientes Especiais do curso de Odontologia da Universidade Cruzeiro do Sul(Unicsul-São Paulo), com lesões na cavidade oral, tratadas com laser de baixa intensidade. Há poucoscasos relatados na literatura de lesões de EB na cavidade oral, e a forma de manejo desses pacientespelo cirurgião-dentista. O artigo discute também aspectos relacionados à sua definição, ao diagnóstico,à etiologia e ao tratamento dessa alteração, indicando a laserterapia como alternativa no tratamentosintomático das EB.

The authors present a case of epidermolysis bullosa (EB), attended the clinic of the discipline ofdentistry for special patients the course of Dentistry, University Cruzeiro do Sul (Unicsul-Sao Paulo),with lesions in the oral cavity treated with low-level laser intensity. There are few cases reported in theliterature of EB lesions in the oral cavity, and how to manage these patients by dentists. The article alsodiscusses issues related to its definition, diagnosis, etiology and treatment of this amendment, indicatingthe laser therapy as an alternative in the symptomatic treatment of EB.

The Birmingham Epidermolysis Bullosa Severity score: development and validation.

BACKGROUND: Objective severity scores facilitate clinical care and research. However, the rarity and heterogeneity of epidermolysis bullosa (EB) make scoring difficult. OBJECTIVES: To develop a severity score covering all subtypes of EB at all ages that is simple, valid, sensitive and reliable. METHODS: Score items and weightings were generated by expert consensus, and refined for content and face validity. The Birmingham EB Severity (BEBS) score was tested on 97 patients aged 0-64 years. RESULTS: Eleven items were scored: area of damaged skin, involvement of nails, mouth, eyes, larynx and oesophagus, scarring of hands, skin cancer, chronic wounds, alopecia and nutritional compromise. Area was allocated 50 points, and the 10 other items 5 points each, giving a maximum score of 100. Lowest BEBS scores occurred in Weber-Cockayne EB simplex (median 1.0; range 0.1-3.0; n = 12), highest scores in generalized non-Herlitz junctional EB (28.5; 5.0-62.0; n = 7), Hallopeau-Siemens recessive dystrophic EB (HS-RDEB) (22.9; 4.3-69.0; n = 23) and Herlitz junctional EB (H-JEB) (14.4; 2.5-49.3; n = 9), and intermediate scores in dominant dystrophic EB (5.3; 0.5-15.9; n = 19), Dowling-Meara EB simplex (DM-EBS) (6.3; 2.8-22.5; n = 16) and non-Hallopeau-Siemens recessive dystrophic EB (7.8, 2.8-27.8; n = 11). Intra- and interobserver correlations were high. With age, scores increased for H-JEB (r = 0.9, P = 0.001) and HS-RDEB (r = 0.73, P = 0.001) and decreased for DM-EBS (r = -0.62, P = 0.01), with positive but nonsignificant correlations for the other types. CONCLUSIONS: The BEBS score appears valid and reproducible, gives appropriate scores for different subtypes, and reflects changes with age.

Epidermolisis Bulosa: revisión bibliográfica, 2008 / Bullosa epidermolysis: bibliographical revision, 2008

El término epidermolisis bullosa fue sellado por Köbneren 1886.” La misma engloba un grupo heterogéneo de enfermedades hereditarias raras de la piel por alteraciones en los genes responsables de la formación de la epidermis y dermis. La alteración genética que causa la enfermedad puede ser heredada debido a una mutación genética durante el embarazo (de novo). Se caracteriza por una erupción de ampollas en la piel de forma espontánea o por traumatismos mínimos, ampollas que al romperse pueden producir lesiones hemorrágicas. Los enfermos de epidermólisis bullosa tienen la piel tan frágil como las alas de una mariposa, por eso los niños que la padecen son conocidos como niños mariposa.(AU)

Control of organ transplant-associated graft-versus-host disease by activated host lymphocyte infusions.

BACKGROUND: Prolonged persistence of donor-derived T cells after organ transplantation has been proposed to improve long-term allograft survival. However, surviving transplant-derived T cells are also able to mediate devastating graft-versus-host disease (GvHD). Currently, GvHD after organ transplantation is usually refractory to conventional therapy and the disease outcome fatal. METHODS: Graft-reactive host T cells were generated ex vivo from a patient suffering from a severe and refractory liver-transplant-associated GvHD. To control GvHD, activated alloreactive host T cells were repetitively retransferred into the patient (activated host lymphocyte infusion [aHLI]). RESULTS: Adoptive transfer of ex vivo activated alloreactive host T cells (aHLI) led to the control and complete resolution of severe GvHD without inducing allograft rejection. CONCLUSIONS: aHLI opens a novel therapeutic window to control solid-organ transplant-associated GvHD while preserving allograft integrity.

Considerações no atendimento ao paciente infantil portador de epidermólise bolhosa / Considerations in the management to the pediatric patient carrier bullosa epidermolysis

A epidermólise bolhosa representa um grupo de desordens dermatológicas, caracterizadas pela fragilidade da pele e mucosas na formação de bolhas e vesículas, que ulceram e restringem a qualidade de vida destes pacientes. O envolvimento da cavidade bucal é, dependendo do subtipo, manifestado por bolhas e úlceras na mucosa bucal, língua e palato e, por anomalias na formação dentária. A sintomatologia das úlceras dificulta a higiene bucal, favorecendo o acúmulo do biofilme dentário, presença de doenças periodontais e evolução das lesões cariosas, bem como a alimentação prejudicada, favorecendo a desnutrição. As dificuldades no atendimento e no tratamento odontológico do paciente portador de epidermólise bolhosa são conhecidas. O cirurgião-dentista ou o odontopediatra desempenha um papel fundamental na qualidade de vida destes pacientes. O propósito deste trabalho foi o de discutir as condutas inerentes ao atendimento odontológico, principalmente no paciente infantil

Homozygous protein C deficiency with purpura fulminans: report of a new case and a description of a novel mutation.

We report here a quite rare case of severe homozygous protein C deficiency. The index case is a 9-month-old Saudi boy who was born after an uneventful pregnancy at 39 weeks. The diagnosis of epidermoloysis bullosa and the appearance of scrotal haematoma raised the diagnosis of thrombosis due to protein C deficiency. The clinical presentation and extremely low level of protein C activity (< 0.01 U/ml) in the index case suggested a severe case of protein C deficiency. The father is 28 years old and the mother is 25 years old and are consanguineous. Neither had a personal or family history of thrombosis. Genomic DNA was extracted from peripheral blood of the patient and both parents, exons of protein C were amplified by polymerase chain reaction and sequenced. Sequencing revealed the presence of a novel CCTG duplicate nucleotide (effective insertion) after nucleotide 8826 in exon 9 of the protein C gene. This insertion is found in the homozygous state in the patient and in the heterozygous state in both parents. It results in a frame-shift mutation, which introduces a stop-codon, thereby generating a prematurely truncated protein. These molecular findings agree with the presence of quantitative protein C deficiency in the index case.

Genetic abnormalities and clinical classification of epidermolysis bullosa.

Genetic abnormalities for different subtypes of epidermolysis bullosa (EB) have been described. In dominant simplex type EB, mutations of the K5 or K14 gene lead to disruption of basal cells and the formation of bullae. The recessive simplex types include EB with muscular dystrophy due to abnormal plectin, EB without muscular dystrophy in patients homozygous for K14 gene abnormalities, and skin fragility syndrome, with formation of acantholytic vesicles within the epidermis due to PKP1 gene mutations. In junctional EB, mutations of the laminin 5, type XVII collagen, and alpha 6 beta 4 integrin genes have been reported. Dystrophic type EB is associated with various abnormalities of the type VII collagen gene. A new classification of EB based on these genetic abnormalities has been proposed. However, some concern has been voiced regarding the clinical utility of a classification based solely on genetic abnormalities. Although the reasons are unclear, identical genetic abnormalities have been known to be associated with different clinical features. A classification including a component based on clinical features would therefore be preferable. This article describes recently discovered genetic abnormalities and offers a new classification scheme for EB.