Treatment Of Epidermolysis Bullosa Research Articles

Deficient skin proteins rescue of expression in patients with epidermolysis bullosa: efficacy of gentamicin

Epidermolysis bullosa is a group of rare hereditary skin diseases based on mutations in the genes of structural proteins of the epidermis and the dermal-epidermal junction. Clinically, epidermolysis bullosa is characterized by the appearance of erosions and blisters on the skin and mucous membranes in response to any minor impact. Currently, the treatment of epidermolysis bullosa is only symptomatic. Pathogenetic methods of the epidermolysis bullosa therapy are under development. One of the new possible pathogenetic directions in the treatment of epidermolysis bullosa is aminoglycoside antibiotics (gentamicin, geneticin, paromomycin). A number of studies have shown the ability of gentamicin to promote readthrough terminating codon and resume the synthesis of type VII collagen in keratinocytes and fibroblasts in patients with epidermolysis bullosa with nonsense mutations in the COL7A1. The review presented the possibilities of gentamicin therapy for patients with epidermolysis bullosa, describes the mechanism of its action, summarizes data from clinical trials.

Gene-edited cells: novel allogeneic gene/cell therapy for epidermolysis bullosa.

Epidermolysis bullosa (EB) is a group of rare genetic skin fragility disorders, which are hereditary. These disorders are associated with mutations in at least 16 genes that encode components of the epidermal adhesion complex. Currently, there are no effective treatments for this disorder. All current treatment approaches focus on topical treatments to prevent complications and infections. In recent years, significant progress has been achieved in the treatment of the severe genetic skin blistering condition known as EB through preclinical and clinical advancements. Promising developments have emerged in the areas of protein and cell therapies, such as allogeneic stem cell transplantation; in addition, RNA-based therapies and gene therapy approaches have also become a reality. Stem cells obtained from embryonic or adult tissues, including the skin, are undifferentiated cells with the ability to generate, maintain, and replace fully developed cells and tissues. Recent advancements in preclinical and clinical research have significantly enhanced stem cell therapy, presenting a promising treatment option for various diseases that are not effectively addressed by current medical treatments. Different types of stem cells such as primarily hematopoietic and mesenchymal, obtained from the patient or from a donor, have been utilized to treat severe forms of diseases, each with some beneficial effects. In addition, extensive research has shown that gene transfer methods targeting allogeneic and autologous epidermal stem cells to replace or correct the defective gene are promising. These methods can regenerate and restore the adhesion of primary keratinocytes in EB patients. The long-term treatment of skin lesions in a small number of patients has shown promising results through the transplantation of skin grafts produced from gene-corrected autologous epidermal stem cells. This article attempts to summarize the current situation, potential development prospects, and some of the challenges related to the cell therapy approach for EB treatment.

Advances in Treatments for Epidermolysis Bullosa (EB): Emphasis on Stem Cell-Based Therapy.

Epidermolysis bullosa (EB) is a rare genetic dermatosis characterized by skin fragility and blister formation. With a wide phenotypic spectrum and potential extracutaneous manifestations, EB poses significant morbidity and mortality risks. Currently classified into four main subtypes based on the level of skin cleavage, EB is caused by genetic mutations affecting proteins crucial for maintaining skin integrity. The management of EB primarily focuses on preventing complications and treating symptoms through wound care, pain management, and other supportive measures. However, recent advancements in the fields of stem cell therapy, tissue engineering, and gene therapy have shown promise as potential treatments for EB. Stem cells capable of differentiating into skin cells, have demonstrated positive outcomes in preclinical and early clinical trials by promoting wound healing and reducing inflammation. Gene therapy, on the other hand, aims to correct the underlying genetic defects responsible for EB by introducing functional copies of mutated genes or modifying existing genes to restore protein function. Particularly for severe subtypes like Recessive Dystrophic Epidermolysis Bullosa (RDEB), gene therapy holds significant potential. This review aims to evaluate the role of new therapeutic approaches in the treatment of EB. The review includes findings from studies conducted on humans. While early studies and clinical trials have shown promising results, further research and trials are necessary to establish the safety and efficacy of these innovative approaches for EB treatment.

Oleogel-S10 in Dystrophic Epidermolysis Bullosa: A Case Series Evaluating the Impact on Wound Burden Over Two Years.

Epidermolysis bullosa (EB) is a group of rare, difficult-to-treat, inherited multisystem diseases affecting epithelial integrity. Impaired wound healing is central and can lead to serious clinical complications, deformities, and symptoms with a devastating impact on quality of life (QoL). Dressing changes and wound care are central to the management of EB. Recently Oleogel-S10 (also known as birch bark extract or birch triterpenes) was approved in Europe and the UK for treating EB wounds. This approval was based on data from the EASE phase3 study, which demonstrated Oleogel-S10 accelerated wound healing, reduced total wound burden, and decreased the frequency of dressing changes in patients with EB. A retrospective analysis of medical records was conducted for up to 24months in 13 patients with EB treated with Oleogel-S10 through an early access programme in Colombia. Effectiveness was assessed by measuring body surface area percentage (BSAP) and total body wound burden (EBDASI). Tolerability and safety were monitored throughout. This is the first report to evaluate the effectiveness of Oleogel-S10 in clinical practice. The results showed a reduction in percentage of BSA affected, from a mean of 27.3% at baseline to 10.4% at 24-month follow-up, despite treatment interruptions. A reduction in EBDASI skin activity score of - 16.2 (24months) together with a reduced skin damage index score of - 15.4 (18months) was also observed. Physicians, patients, and caregivers perceived faster wound closure. Adherence with therapy by patients was good, and patients expressed satisfaction with treatment and reported improvements in self-esteem, productivity, and social interaction. Oleogel-S10 was well tolerated; however, two patients reported worsening wounds related to gauze adherence. Two deaths during treatment interruption were reported and was not considered related to Oleogel-S10. This study supports the effectiveness of Oleogel-S10 in a real-world scenario in a country with scarce resources for the treatment of EB.

Dystonin modifiers of junctional epidermolysis bullosa and models of epidermolysis bullosa simplex without dystonia musculorum.

The Lamc2jeb junctional epidermolysis bullosa (EB) mouse model has been used to demonstrate that significant genetic modification of EB symptoms is possible, identifying as modifiers Col17a1 and six other quantitative trait loci, several with strong candidate genes including dystonin (Dst/Bpag1). Here, CRISPR/Cas9 was used to alter exon 23 in mouse skin specific isoform Dst-e (Ensembl GRCm38 transcript name Dst-213, transcript ID ENSMUST00000183302.5, protein size 2639AA) and validate a proposed arginine/glutamine difference at amino acid p1226 in B6 versus 129 mice as a modifier of EB. Frame shift deletions (FSD) in mouse Dst-e exon 23 (Dst-eFSD/FSD) were also identified that cause mice carrying wild-type Lamc2 to develop a phenotype similar to human EB simplex without dystonia musculorum. When combined, Dst-eFSD/FSD modifies Lamc2jeb/jeb (FSD+jeb) induced disease in unexpected ways implicating an altered balance between DST-e (BPAG1e) and a rarely reported rodless DST-eS (BPAG1eS) in epithelium as a possible mechanism. Further, FSD+jeb mice with pinnae removed are found to provide a test bed for studying internal epithelium EB disease and treatment without severe skin disease as a limiting factor while also revealing and accelerating significant nasopharynx symptoms present but not previously noted in Lamc2jeb/jeb mice.

Analysis of the state and problems of pharmaceutical supply for patients with epidermolysis bullosa

Aim. To analyze medical technologies (MT) for the treatment of epidermolysis bullosa (EB) and their availability to patients and the healthcare system.
 Materials and methods. The study objects were scientific publications, normative legal acts, guidelines (protocols), statistical data, the Orphanet network, official data of the Ministry of Health and the State Enterprise “Medical Procurement of Ukraine”, marketing information. The methods of content analysis, structural and logical, comparison, generalization, marketing analysis were used.
 Results. Modern approaches to the classification of types of EB were studied; epidemiological indicators were analyzed; recommendations of clinical protocols were summarized. It has been found that currently there are no available specific MT in the world for the treatment of this severe chronic disease. International clinical guidelines recommend the use of medicines and medical products to relieve symptoms (wound care, reduce pain and itching), prevent secondary pathologies and improve the quality of life of patients with EB. The cost of treating EB depends on the severity of the disease and the patient’s age. The burden of the disease and the impact on the budget are assessed to be high. The state cannot provide 100 % of the need for the necessary medicines and medical products due to budget constraints. The analysis of the national legal framework for providing patients with rare (orphan) diseases, including EB, with the necessary medicines and medical products was carried out. It has been determined that only 9 INNs of the seven groups of medicines recommended by the protocol are included in the National List and can be purchased for budget funds. The annual need, nomenclature and volumes of purchases of drugs for the treatment of EB were studied. According to the State Enterprise “Medical Procurement of Ukraine” in 2023, for patients with EB it is planned to purchase eight groups of medical products for skin and wound care under 20 names in the amount of UAH 119.8 million.
 Conclusions. In order to improve approaches to the pharmaceutical provision of patients with EB, it is extremely important to use health technology assessment (HTA) to identify the most effective and economically feasible medicines and medical products.

Investigational Treatments for Epidermolysis Bullosa

Epidermolysis bullosa (EB) is a heterogeneous group of rare inherited blistering skin disorders characterized by skin fragility following minor trauma, usually present since birth. EB can be categorized into four classical subtypes, EB simplex, junctional EB, dystrophic EB and Kindler EB, distinguished on clinical features, plane of blister formation in the skin, and molecular pathology. Treatment for EB is mostly supportive, focusing on wound care and patient symptoms such as itch or pain. However, therapeutic advances have also been made in targeting the primary genetic abnormalities as well as the secondary inflammatory footprint of EB. Pre-clinical or clinical testing of gene therapies (gene replacement, gene editing, RNA-based therapy, natural gene therapy), cell-based therapies (fibroblasts, bone marrow transplantation, mesenchymal stromal cells, induced pluripotential stem cells), recombinant protein therapies, and small molecule and drug repurposing approaches, have generated new hope for better patient care. In this article, we review advances in translational research that are impacting on the quality of life for people living with different forms of EB and which offer hope for improved clinical management.

Review of the Latest Methods of Epidermolysis Bullosa and Other Chronic Wounds Treatment Including BIOOPA Dressing

Epidermolysis bullosa (EB) is a hereditary genetic skin disorder, classified as a type of genodermatosis, which causes severe, chronic skin blisters associated with painful and potentially life-threatening complications. Currently, there is no effective therapy or cure for EB. However, over the past decade, there have been several important advances in treatment methods, which are now approaching clinical application, including gene therapy, protein replacement therapy, cell therapy (allogeneic fibroblasts, mesenchymal stromal cells), bone marrow stem cell transplant, culture/vaccination of revertant mosaic keratinocytes, gene editing/engineering, and the clinical application of inducible pluripotent stem cells. Tissue engineering scientists are developing materials that mimic the structure and natural healing process to promote skin reconstruction in the event of an incurable injury. Although a cure for EB remains elusive, recent data from animal models and preliminary human clinical trials have raised the expectations of patients, clinicians, and researchers, where modifying the disease and improving patients’ quality of life are now considered attainable goals. In addition, the lessons learned from the treatment of EB may improve the treatment of other genetic diseases.

Опыт лечения плоскоклеточного рака кожи у пациентов с дистрофической формой буллезного эпидермолиза

Epidermolysis bullosa (EB) is a hereditary, heterogeneous group of rare genetic dermatoses characterized by the skin and mucous membranes fragility. One of the most severe forms of the disease is dystrophic EB, the severity of which is due to the generalized nature of the lesion of the skin and mucous membranes of internal organs. In the absence of pathogenetic treatment of EB, multidisciplinary care is aimed at minimizing the risk of progression of skin lesions, relieving symptoms and specific complications. One of the most dangerous complications of EB is the early development of squamous cell skin cancer (SCC), which is especially characteristic for patients with dystrophic form. There are no generally accepted recommendations for the systemic therapy of SCC in EB, as well as clear evidence of the cytotoxic drugs clinical effectiveness in the treatment of this group of patients. The presented in the article experience of treatment of both localized and widespread forms of SCC in patients with dystrophic form of EB shows the possibilities of the surgical approach and the systemic therapy effectiveness. Of course, any experience in the treatment of a malignant tumor with such a severe orphan disease is of great value and can help in the selection of the most effective treatment tactics in the future.

Pathogenetic Therapy of Epidermolysis Bullosa: Current State and Prospects.

Epidermolysis bullosa is a severe hereditary disease caused by mutations in genes encoding cutaneous basement membrane proteins. These mutations lead to dermal-epidermal junction failure and, as a result, to disturbances in the morphological integrity of the skin. Clinically, it manifests in the formation of blisters on the skin or mucosa that in some cases can turn into non-healing chronic wounds, which not only impairs patient's quality of life, but also is a live-threatening condition. Now, the main approaches in the treatment of epidermolysis bullosa are symptomatic therapy and palliative care, though they are little effective and are aimed at reducing the pain, but not to complete recovery. In light of this, the development of new treatment approaches aimed at correction of genetic defects is in progress. Various methods based on genetic engineering technologies, transplantation of autologous skin cells, progenitor skin cells, as well as hematopoietic and mesenchymal stem cells are studied. This review analyzes the pathogenetic methods developed for epidermolysis bullosa treatment based on the latest achievements of molecular genetics and cellular technologies, and discusses the prospects for the use of these technologies for the therapy of epidermolysis bullosa.

Intravenous Injection of Muse Cells as a Potential Therapeutic Approach for Epidermolysis Bullosa

Intravenous Injection of Muse Cells as a Potential Therapeutic Approach for Epidermolysis Bullosa

Clinic, diagnostics and treatment of epidermolysis bullosa

Clinic, diagnostics and treatment of epidermolysis bullosa

Orphan designation: antisense oligonucleotide targeting exon 73 in the COL7A1 gene, Treatment of epidermolysis bullosa

Orphan designation: antisense oligonucleotide targeting exon 73 in the COL7A1 gene, Treatment of epidermolysis bullosa

Orphan designation: Allogeneic skin-derived ABCB5-positive mesenchymal stem cells, Treatment of epidermolysis bullosa

Orphan designation: Allogeneic skin-derived ABCB5-positive mesenchymal stem cells, Treatment of epidermolysis bullosa

Providing Comprehensive Care to Patients with Epidermolysis Bullosa in the Perioperative Environment

The University of Minnesota Medical Center and Masonic Children’s Hospital EB Center offers comprehensive multidisciplinary care to children with Epidermolysis Bullosa (EB). This is the only center in the United States to offer Bone Marrow Transplantation (BMT) as a treatment for EB. To determine candidacy, these patients come to the Operating Room to have their dressings fully removed, labs drawn, photographs taken and skin biopsies collected under general anesthesia. The child is transported to PACU and remains under sedation while dressings are reapplied, often a 2-3 hour process. Since these patients are at high risk for severe blistering skin injuries, it was evident that modifications to equipment, practice changes, and staff education needed to occur to keep them safe during critical times in Perioperative Services when their usual expert care provider, often a parent, is not present.

Orphan designation: losartan, Treatment of epidermolysis bullosa

Orphan designation: losartan, Treatment of epidermolysis bullosa

Orphan designation: losartan, Treatment of epidermolysis bullosa

Orphan designation: losartan, Treatment of epidermolysis bullosa

Advances in stem cell-based regenerative medicine: Despite setbacks and failures, therapies to replace damaged tissue are making their way into the clinic.

EMBO Reports (2019) e48172 Stem cell‐based regenerative medicine has experienced turbulent times in recent years that have involved several scandals implicating prominent institutions and numerous retractions of papers from leading journals. But it has also seen real progress being made on the way to the clinic. It reflects the tension between human ambition and hope on one side and the need for hard evidence and solid data on the other side in a field where early expectations ran far ahead of reality. This tension may help explain the recent scandal involving stem cell surgeon Paolo Macchiarini, who was found guilty of scientific misconduct regarding an article in The Lancet , which has since been retracted. It is an ongoing saga as Macchiarini is still publishing in leading journals, even though his reputation as a surgeon and stem cell researcher has been compromised. > … the whole field of regenerative medicine had been tainted by a number of cases where […] researchers had taken short cuts and neglected basic science. The story dates back to 2004, when Macchiarini's team extracted some pig intestine and removed the cells to leave a collagen matrix that was then repopulated with muscle and fibroblasts to generate connective epidermal tissue. The patch was implanted in the airway of a 58‐year‐old patient suffering from respiratory problems after surgery for lung cancer [1]. Macchiarini then expanded this technique to whole tracheas using plastic scaffolds in addition to natural tissue from human donors. In another clinical case, the bare plastic scaffold was populated with stem cells taken from the patient's own bone marrow and implanted in a young female patient in 2008. This propelled Macchiarini almost to rock star status and an appointment by the Karolinska Institute, where he refined his technique by replacing donor windpipes with plastic …

1385 Dual mechanism of Type VII collagen transfer by bone marrow mesenchymal stem cell extracellular vesicles to recessive dystrophic epidermolysis bullosa fibroblasts

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe blistering disease resulting from a lack of type VII collagen production. Recent clinical trials have shown efficacy of bone marrow-derived stem cells (BM-MSCs) in the treatment of epidermolysis bullosa, including improved basement membrane restructuring and cutaneous wound healing. The mechanism as to how type VII collagen is transferred from donor stem cell to recipient RDEB cells has not been defined. Here, we report that BM-MSC-derived extracellular vesicles serve at least two roles: 1) to help transport the insoluble type VII collagen alpha chains within the extracellular space; and 2) to feed RDEB fibroblasts with messenger RNA that codes for type VII collagen, resulting in COL7A1 translation and synthesis of normal type VII collagen alpha chain proteins, eventually secreted by RDEB fibroblasts. Utilizing a chemoselective ligation detection method, we found RDEB cells that were treated simultaneously with BM-MSC EVs and an L-methionine analog, L-homopropargylglycine (HPG), synthesized collagen VII alpha chain protein that contained the alkyne group of HPG to react (i.e. undergo the Click-iT® reaction) with azide-modified Alexa 594, enabling detection and suggesting de novo synthesis of type VII collagen by RDEB fibroblasts. These dual mechanisms could result in a net positive “transfer” of type VII collagen to the extracellular environment of skin in RDEB patients, likely improving both basement membrane integrity and wound healing. Therapies that utilize EVs to enhance delivery of type VII collagen, both in terms of nucleic acids and protein, have potential to improve the functions of skin in RDEB patients.

Dual mechanism of type VII collagen transfer by bone marrow mesenchymal stem cell extracellular vesicles to recessive dystrophic epidermolysis bullosa fibroblasts

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe blistering disease resulting from a lack of type VII collagen production. Recent clinical trials have shown efficacy of bone marrow-derived mesenchymal stem cells (BM-MSCs) in the treatment of epidermolysis bullosa, including improved basement membrane restructuring and cutaneous wound healing. The mechanism as to how type VII collagen is transferred from donor stem cell to recipient RDEB cells has not been defined. Here, we submit the model that BM-MSC-derived extracellular vesicles serve at least two roles: 1) to help transport type VII collagen within the extracellular space; and 2) to feed RDEB fibroblasts with messenger RNA that codes for type VII collagen, resulting in COL7A1 translation and synthesis of type VII collagen alpha chain proteins by RDEB fibroblasts. Utilizing a chemoselective ligation detection method, we found RDEB cells that were treated simultaneously with BM-MSC EVs and an l-methionine analog, l-homopropargylglycine (HPG), synthesized collagen VII alpha chain protein that contained the alkyne group of HPG to react (i.e. undergo the Click-iT® reaction) with azide-modified Alexa 594, suggesting de novo synthesis of type VII collagen by RDEB fibroblasts. Thus, our results support a model in which BM-MSC EVs help increase type VII collagen levels available to recipient cells by 1) donating BM-MSC type VII collagen protein and 2) inducing RDEB fibroblasts to make their own type VII collagen protein. These findings allow us to hypothesize that the secretome of BM-MSCs could have therapeutic value in the treatment of RDEB-related skin disorders.