From Supportive Care to Precision Medicine: Emerging Therapies for Inherited Epidermolysis Bullosa

1. Introduction

Inherited epidermolysis bullosa (EB) comprises a heterogeneous group of rare monogenic disorders characterised by marked mechanical fragility of the skin and mucous membranes, resulting in blistering and tissue injury following minimal trauma [1,2,3,4,5]. Disease severity varies widely according to the affected gene and level of tissue cleavage, ranging from relatively mild phenotypes with localised cutaneous involvement to severe multisystem disease characterised by chronic wounds, progressive scarring, extracutaneous complications and premature mortality. Despite its rarity, EB remains one of the most challenging inherited disorders encountered in clinical practice because of its lifelong course, complex multisystem manifestations and profound burden on affected children and their families.

For decades, the management of EB relied almost exclusively on multidisciplinary supportive care, including advanced wound care, nutritional support, infection prevention, pain management and surveillance for systemic complications. Although these interventions have improved survival and quality of life, particularly in patients with severe phenotypes, they neither correct the underlying genetic defect nor prevent disease progression. Therapeutic development has therefore increasingly shifted from symptom control towards strategies that directly address the molecular mechanisms underlying EB [1,2,3,4,5].

Advances in molecular genetics have transformed the understanding of EB from that of a predominantly clinicopathological entity into a group of genetically defined disorders, thereby providing a foundation for precision medicine. Gene replacement, RNA-based therapies, protein replacement, cell-based regenerative approaches and genome editing have rapidly broadened the therapeutic landscape, with some strategies progressing from preclinical investigation to clinical application and regulatory approval in selected EB subtypes. Collectively, these developments have reshaped the therapeutic outlook for EB by introducing the possibility of modifying its natural history rather than solely alleviating its clinical manifestations [2,3,4,5,6,7,8,9,10].

In this narrative review, we provide an overview of the biological rationale, current evidence and principal challenges associated with established and emerging disease-modifying therapies for inherited EB. Particular emphasis is placed on recent advances in gene-, RNA-, protein- and cell-based approaches and on their potential application in clinical practice. We also discuss the limitations of the available evidence and the key barriers to translating these innovative strategies into safe, effective and accessible long-term treatments.

2. Methods

A narrative literature review was conducted to provide an updated overview of current and emerging therapeutic strategies for EB, with particular emphasis on their biological rationale, clinical evidence, safety and tolerability, and potential applicability in paediatric patients.

The literature was searched using PubMed/MEDLINE and supplemented by manual screening of the reference lists of relevant articles, clinical practice guidelines, consensus statements and key reviews. The search combined terms relating to inherited EB and its major subtypes with terms describing established and emerging therapeutic approaches. Search terms included “epidermolysis bullosa,” “epidermolysis bullosa simplex,” “junctional epidermolysis bullosa,” “dystrophic epidermolysis bullosa,” “Kindler epidermolysis bullosa,” “gene therapy,” “gene replacement,” “RNA therapy,” “protein replacement,” “cell therapy,” “stem cells,” “genome editing,” “CRISPR,” and “wound healing”.

Relevant peer-reviewed publications and authoritative clinical or regulatory documents were considered. These included clinical trials, observational studies, consensus recommendations, clinical practice guidelines and, where appropriate, selected preclinical studies addressing emerging therapeutic strategies. Particular attention was given to approved and clinically advanced treatments, including topical pharmacological therapies, in vivo gene therapy and ex vivo gene-corrected epidermal grafts, as well as investigational cell-, RNA-, protein- and genome-editing-based approaches.

Publications were selected for their relevance to therapeutic efficacy, wound healing, safety and tolerability, durability of response, mechanisms of action, molecular correction, applicability to paediatric populations and practical limitations. Regulatory documents issued by relevant authorities were also reviewed to determine the approval status and current clinical positioning of advanced therapies.

Given the heterogeneity of the available evidence, the differing stages of clinical development of the therapies examined and the narrative design of this review, no quantitative meta-analysis was undertaken. The evidence was synthesised qualitatively, with emphasis on the evolving transition from conventional supportive care towards precision, regenerative and molecularly targeted therapeutic strategies.

3. Molecular Pathogenesis: Biological Basis for Precision Therapies

EB is caused by pathogenic variants in genes encoding structural and regulatory proteins essential for dermal–epidermal adhesion and tissue integrity. More than 20 causative genes have been identified, resulting in a broad spectrum of phenotypes that vary in clinical severity, inheritance pattern and extent of extracutaneous involvement. According to the current molecular classification, EB comprises four major categories: epidermolysis bullosa simplex (EBS), junctional epidermolysis bullosa (JEB), dystrophic epidermolysis bullosa (DEB) and Kindler epidermolysis bullosa (KEB). These categories are distinguished primarily by the level of tissue cleavage and the specific components of the dermal–epidermal junction that are affected [2,3].

The proteins implicated in EB serve functions extending beyond mechanical stability. They also participate in cellular signalling, tissue repair and the interactions among keratinocytes, fibroblasts, immune cells and the extracellular matrix. Their dysfunction therefore initiates a complex cascade of secondary pathogenic events, including persistent inflammation, altered extracellular matrix remodelling, fibrosis and impaired wound healing. Over time, these processes contribute to progressive tissue damage, scarring and the systemic complications associated with severe forms of the disease [1,4].

Disease severity is determined not only by the causative gene and specific pathogenic variant but also by factors such as residual protein expression, genetic modifiers and environmental influences. The interplay among these determinants helps explain the substantial phenotypic variability observed both between and within EB subtypes, including among individuals carrying variants in the same gene. Comprehensive molecular diagnosis has consequently become an essential component of clinical management, enabling accurate classification, informed genetic counselling and the identification of patients who may be eligible for genotype- or mutation-specific therapies [3].

The growing understanding of EB pathogenesis has provided the biological foundation for precision therapeutic strategies designed to intervene at different levels of the disease process. These approaches include correction or replacement of the defective gene, restoration of the missing or dysfunctional protein, regeneration of affected tissues and modulation of downstream pathways involved in inflammation, fibrosis and defective wound repair. This close relationship between molecular diagnosis and targeted treatment has established EB as an important model for the development of precision and regenerative medicine in dermatology [4,6,7,8,9].

4. Clinical Burden and Unmet Therapeutic Needs

Although the severity and spectrum of clinical manifestations vary considerably among EB subtypes, recurrent blistering, chronic wounds and progressive scarring are central features of the disease and account for substantial lifelong morbidity. Patients may experience persistent or recurrent pain, pruritus, infections, anaemia, nutritional impairment and progressive musculoskeletal disability. Severe disease can also involve the gastrointestinal, ocular, oral, genitourinary and respiratory systems, further increasing the complexity of clinical management. Moreover, individuals with severe recessive dystrophic EB face a markedly increased risk of developing early-onset, aggressive cutaneous squamous cell carcinoma, which remains a major cause of premature mortality in this population [1,11].

The burden of EB extends well beyond its physical manifestations. Daily wound care is painful, time-consuming and resource-intensive, placing substantial emotional and practical demands on patients and their caregivers. Recurrent injuries, visible skin involvement and functional limitations may restrict autonomy, social participation and school or work activities, with important consequences for psychological well-being and family life. These dimensions are supported by the recent QoL-REB exploratory, cross-sectional, patient-led study involving children and adults with EB, which documented substantial limitations in autonomy, psychological well-being and participation in everyday life [12].

Despite major advances in multidisciplinary supportive care, treatment remains largely symptom-directed and is unable to prevent the continued development of chronic inflammation, fibrosis, scarring and irreversible tissue damage. In addition, the rarity and molecular heterogeneity of EB, together with the challenges of achieving durable treatment effects across extensive cutaneous and extracutaneous tissues, complicate the development and evaluation of new therapies. Important unmet needs therefore include treatments that are effective, safe, durable, broadly accessible and capable of addressing both local and systemic disease manifestations. These limitations provide a strong rationale for the development of disease-modifying strategies that can alter the natural history of EB rather than solely mitigate its consequences [4,6,7,8,9].

5. Current Standards of Care

Comprehensive multidisciplinary supportive care remains the cornerstone of EB management. International guidelines recommend an individualised and integrated approach delivered by experienced multidisciplinary teams. Core components include specialised wound care, prevention and treatment of infection, pain and pruritus management, nutritional support, rehabilitation, surveillance for extracutaneous complications and psychosocial assistance. Management should also incorporate age-appropriate education and support for patients and caregivers, as well as coordinated transition from paediatric to adult services [13,14,15,16].

Wound care requires particular attention because dressing changes may themselves cause pain and additional skin trauma. Management should therefore aim to promote wound healing, reduce friction, control exudate, prevent infection and minimise procedural discomfort. Nutritional assessment and supplementation are frequently required because chronic inflammation, increased metabolic demands, oral involvement and oesophageal complications can impair growth and nutritional status. Regular surveillance is also essential for the early identification and management of complications such as anaemia, contractures, osteoporosis, renal or cardiac involvement and cutaneous squamous cell carcinoma.

Although these interventions have improved survival, symptom control and quality of life, they do not correct the underlying molecular defect and remain associated with a substantial treatment burden. Disease-modifying therapies should therefore be viewed as complementary to, rather than replacements for, established supportive care. The future management of EB will probably require an integrated model that combines molecularly targeted or regenerative therapies with comprehensive, multidisciplinary long-term care, thereby addressing both the primary disease mechanism and its secondary complications [4,6,7,8,9].

6. Transition to Disease-Modifying Therapies and Paediatric Considerations

The therapeutic landscape of inherited EB is shifting from exclusively supportive care towards interventions that target wound-healing pathways or the underlying molecular defect. Recessive dystrophic epidermolysis bullosa (RDEB) has become a major focus of therapeutic development because the absence or severe dysfunction of type VII collagen, encoded by COL7A1, compromises the anchoring fibrils that connect the epidermis to the underlying dermis. Even partial restoration of type VII collagen may improve dermal–epidermal adhesion and promote sustained wound healing, providing a strong biological rationale for gene-, cell- and protein-based therapeutic strategies [17,18].

The goals of treatment extend beyond the closure of individual wounds. Early intervention may reduce cumulative tissue injury during growth, limit chronic inflammation and fibrosis, preserve mobility, decrease pain and analgesic requirements, support adequate nutrition and facilitate psychosocial development. Efficacy should therefore be assessed using multidimensional outcomes that include wound closure and recurrence, pain and pruritus, physical function, patient-reported outcomes, quality of life and caregiver burden; recent patient-led evidence indicates that such measures are needed to capture impacts on autonomy and everyday participation that wound closure alone may not fully reflect [12,19,20].

Evaluation of treatment response is complicated by the marked heterogeneity of EB wounds. A single patient may simultaneously present acute traumatic lesions, recurrent wounds, chronic non-healing ulcers, infected areas and fibrotic scars exposed to different degrees of mechanical stress. Therapeutic efficacy observed in one lesion cannot necessarily be generalised to the entire cutaneous disease burden. Clinical trials have therefore increasingly adopted wound-specific endpoints and intrapatient comparisons, in which treated and control wounds are evaluated within the same participant, to reduce the influence of interindividual variability [21].

Recent regulatory approvals have introduced three distinct therapeutic approaches: enhancement of endogenous wound repair with Oleogel-S10, topical COL7A1 gene replacement with beremagene geperpavec and ex vivo correction of autologous keratinocytes with prademagene zamikeracel. Their principal characteristics are summarised in Table 1.

These interventions should not be considered curative. Each acts at a different level of disease pathogenesis and has distinct advantages and limitations regarding durability, feasibility, manufacturing complexity, cost and applicability across EB subtypes. Treatment selection should therefore be individualised according to molecular diagnosis, age, disease severity, wound characteristics, treatment accessibility and patient and family preferences [10,21].

Several issues assume particular importance in children. Treatment initiated during infancy or childhood may be continued for many years, making long-term safety and durability essential considerations. Young children may also require analgesia or sedation for extensive dressing changes and surgical procedures, while their rapid growth and wound turnover may influence treatment frequency and graft durability. Long-term registries and post-authorisation surveillance will therefore be essential for defining the effects of these therapies across the lifespan [20,21].

7. Approved and Clinically Advanced Therapies

7.1. Oleogel-S10 (Filsuvez®)

7.1.1. Mechanism and Biological Rationale

Oleogel-S10 is a topical gel containing a dry extract of Betula pendula bark enriched in pentacyclic triterpenes, principally betulin, together with betulinic acid, lupeol, erythrodiol and oleanolic acid [22]. These compounds modulate several phases of wound healing by influencing inflammatory responses, promoting keratinocyte migration and differentiation, stimulating fibroblast activity and accelerating re-epithelialisation [22,23].

Unlike gene- or protein-replacement strategies, Oleogel-S10 does not target the causative mutation. Instead, it enhances endogenous tissue-repair mechanisms and is therefore not restricted to a specific genotype. Its approval represented an important transition from conventional dressings alone towards pharmacological modulation of wound healing in EB [24,25].

7.1.2. Clinical Evidence

The efficacy and safety of Oleogel-S10 were evaluated in the international phase III EASE trial, which enrolled children and adults with junctional EB or dystrophic EB [24]. Participants received Oleogel-S10 or vehicle gel in addition to standard wound care. The primary endpoint was complete closure of a predefined target wound within 45 days; secondary outcomes included time to healing, durability of closure, patient-reported outcomes and safety.

A significantly greater proportion of target wounds treated with Oleogel-S10 achieved complete closure than control-treated wounds. Treatment effects appeared particularly evident in more recent and partial-thickness wounds, suggesting that response may depend on wound characteristics. Chronic fibrotic ulcers may be less responsive because of persistent inflammation, altered extracellular matrix organisation and impaired regenerative capacity.

The inclusion of children in EASE supports the relevance of its findings to paediatric practice. Nevertheless, the trial evaluated selected target wounds rather than the total cutaneous disease burden. The results should therefore be interpreted as evidence of improved healing in treated wounds rather than correction of the systemic disease or its underlying molecular cause.

7.1.3. Safety and Paediatric Applicability

Oleogel-S10 was generally well tolerated, and most reported adverse events were mild or moderate and consistent with complications of EB itself [24]. The absence of clinically relevant systemic toxicity is particularly advantageous in children who may require repeated and prolonged treatment.

The treatment can be incorporated into routine dressing changes and administered at home by appropriately trained caregivers, without specialised equipment, surgery or hospitalisation. Accelerated wound closure may reduce discomfort during dressing changes and potentially decrease the risk of secondary infection, although these additional benefits require further assessment in dedicated paediatric studies.

Long-term observations have supported continued tolerability, without the emergence of major new safety signals [26]. However, treatment does not prevent the development of new blisters after discontinuation because it does not restore the defective adhesion protein.

7.1.4. Limitations and Future Directions

Oleogel-S10 does not correct the underlying genetic defect, restore structural proteins or address extracutaneous manifestations. It is also unknown whether sustained improvements in wound healing can reduce chronic inflammation, fibrosis or the lifetime risk of cutaneous squamous cell carcinoma.

Its mutation-independent mechanism nevertheless makes it relevant to patients who are ineligible for genotype-specific interventions. Future studies should define predictors of response, assess its effect on patient-centred outcomes and investigate its use in combination with gene-, cell- or protein-based therapies.

7.2. Beremagene Geperpavec (B-VEC; Vyjuvek®)

7.2.1. Mechanism and Biological Rationale

Beremagene geperpavec is an in vivo topical gene therapy developed for dystrophic EB caused by pathogenic variants in COL7A1. It delivers functional copies of COL7A1 directly to cutaneous wounds, enabling local production of type VII collagen [10,27,28].

B-VEC uses a genetically modified, replication-defective herpes simplex virus type 1 vector that retains its tropism for keratinocytes and fibroblasts. Following topical application, the vector enters cells within the wound bed and delivers the COL7A1 transgene without integration into the host genome. The resulting type VII collagen is deposited at the dermal–epidermal junction, where it supports anchoring-fibril formation and improves tissue adhesion [10,28].

The non-integrating nature of the vector reduces the theoretical risk of insertional mutagenesis. However, transgene expression is temporary because transduced cells are progressively lost during epidermal turnover, necessitating repeated application.

7.2.2. Clinical Evidence

Initial phase I/II studies demonstrated local restoration of type VII collagen and encouraging wound-healing responses [29]. These findings were subsequently evaluated in the pivotal phase III GEM-3 trial, a randomised, double-blind, placebo-controlled study involving patients with DEB and confirmed pathogenic COL7A1 variants [10].

Paired wounds from each participant were assigned to B-VEC or placebo, allowing each patient to serve as their own control. This design reduced the effect of the substantial clinical variability observed between individuals with EB. At six months, complete wound closure was achieved substantially more frequently in B-VEC-treated wounds than in placebo-treated wounds. Superior closure was also observed at earlier assessment points, indicating that local restoration of type VII collagen can produce clinically meaningful improvements in wound healing.

Reductions in wound-associated pain during dressing changes and favourable patient-reported outcomes were also observed. Although these outcomes were secondary or exploratory, they suggest that successful wound closure may reduce the daily burden of care for patients and families.

7.2.3. Safety and Paediatric Applicability

B-VEC was generally well tolerated. Reported treatment-related events were predominantly mild and included application-site pruritus, local erythema and transient systemic symptoms [10,30]. No vector-related serious adverse events, systemic viral dissemination or treatment-associated malignancies were identified during clinical development. Nevertheless, long-term surveillance remains necessary, particularly when treatment begins early in life.

The topical route avoids surgery and may be incorporated into regular wound-care procedures. Its local action and limited systemic exposure are advantageous in children. Early treatment could theoretically reduce repeated tissue injury and subsequent fibrosis, but whether it modifies these long-term outcomes remains uncertain.

7.2.4. Limitations and Future Directions

B-VEC is restricted to DEB caused by COL7A1 variants and treats only the wounds to which it is applied. It does not correct unaffected but mechanically fragile skin or extracutaneous manifestations such as oesophageal, ocular or musculoskeletal disease. Repeated administration is required because expression is not permanent.

Future research should assess long-term durability, treatment of larger body surface areas, biomarkers of response and combination approaches involving systemic or regenerative therapies. Registry data will also be needed to determine whether sustained healing reduces fibrosis, disability or cutaneous squamous cell carcinoma risk.

7.3. Prademagene Zamikeracel (Zevaskyn™)

7.3.1. Mechanism and Biological Rationale

Prademagene zamikeracel is an ex vivo autologous gene therapy developed for chronic wounds in RDEB. Keratinocytes obtained from a patient’s skin biopsy are transduced with a replication-defective retroviral vector carrying functional COL7A1 cDNA. The corrected cells are expanded under Good Manufacturing Practice conditions and cultured into epidermal sheets for surgical transplantation [31,32].

Following transplantation onto a prepared wound bed, genetically corrected keratinocytes regenerate an epidermis capable of producing type VII collagen at the dermal–epidermal junction. Because epidermal stem cells are included within the graft, the approach has the potential to provide more durable correction than non-integrating topical gene delivery.

This strategy builds on proof-of-concept studies demonstrating long-term epidermal regeneration following transplantation of gene-corrected keratinocyte stem cells in junctional EB [33].

7.3.2. Clinical Evidence

Clinical efficacy was evaluated in the multicentre phase III VIITAL trial, which enrolled patients with chronic RDEB wounds [34,35]. Gene-corrected epidermal grafts produced higher rates of sustained wound closure than standard care, with many treated wounds remaining closed for at least six months. Reductions in pain and pruritus were also reported, indicating benefits extending beyond re-epithelialisation.

Sustained closure of large chronic wounds may be especially valuable in children because these lesions can impair mobility, interfere with sleep and school attendance, and contribute substantially to pain and caregiver burden.

7.3.3. Safety and Paediatric Applicability

The autologous origin of the transplanted keratinocytes minimises the risk of immune rejection. Available clinical evidence indicates an acceptable safety profile, although surgical complications such as graft failure, infection or incomplete engraftment may occur. Continued surveillance is essential because the platform uses an integrating retroviral vector, creating a theoretical risk of insertional genotoxicity [32,35].

Paediatric treatment requires careful consideration of anaesthesia, procedural pain, donor-site selection and the effect of growth on treated areas. The intervention is therefore most appropriate for carefully selected patients managed at highly specialised centres.

7.3.4. Limitations and Future Directions

Manufacturing is individualised, technically complex and time-consuming. Treatment requires specialised laboratory facilities, coordination between manufacturing and clinical teams, preparation of the recipient wound bed and surgical grafting. These requirements restrict accessibility and increase cost.

Treatment is also limited to selected cutaneous areas and does not correct generalised skin fragility or extracutaneous disease. Nevertheless, prademagene zamikeracel provides an important option for selected patients with large, chronic wounds and demonstrates the feasibility of durable epidermal regeneration through ex vivo gene correction.

The principal paediatric implications of these three treatments are compared in Table 2.

8. Emerging Therapeutic Approaches

Currently available therapies remain predominantly local and do not fully address generalised skin fragility or extracutaneous disease. Several emerging strategies are therefore being investigated to provide systemic benefit, restore deficient proteins or achieve permanent correction of pathogenic variants. Their developmental status, potential advantages and principal limitations are summarised in Table 3.

8.1. Mesenchymal Stromal Cell Therapy

Mesenchymal stromal cells (MSCs) are being investigated primarily as a systemic, immunomodulatory treatment for severe RDEB. Their therapeutic effect appears to depend less on persistent engraftment or direct replacement of defective keratinocytes than on the release of paracrine, anti-inflammatory, antifibrotic and pro-regenerative mediators. These include growth factors, cytokines and extracellular vesicles that may modulate macrophage activity, reduce inflammation and promote tissue repair.

Preclinical studies have produced variable results. Although early bone marrow-derived MSC therapy did not prolong survival in Col7a1-deficient mice [36], subsequent intradermal administration promoted type VII collagen deposition, wound regeneration and immature anchoring-fibril formation despite the limited persistence of transplanted cells [39]. ABCB5-positive dermal MSCs have also demonstrated immunomodulatory activity independent of direct type VII collagen replacement [37].

Early clinical studies reported improvements in wound healing, pain, pruritus and inflammatory manifestations following intravenous MSC administration [38,39]. However, the randomised paediatric MissionEB trial did not demonstrate a statistically significant benefit over placebo for its primary endpoint, despite confirming the feasibility and short-term safety of repeated infusions [40]. Clinical studies of ABCB5-positive dermal MSCs have generated encouraging preliminary findings, although confirmation in larger controlled trials is required [41,42].

MSC-derived extracellular vesicles offer a cell-free alternative that may retain some of the regenerative and immunomodulatory effects of parental cells. MUSE cells, a stress-tolerant MSC subpopulation, are also under early investigation [43,44,45]. Across these approaches, major uncertainties include the transient nature of potential benefits, heterogeneity of efficacy measures and the optimal source, dose and frequency of administration.

8.2. Haematopoietic Stem Cell Transplantation

Allogeneic haematopoietic stem cell transplantation (HSCT) represents one of the most intensive systemic approaches investigated in RDEB. Donor bone marrow-derived cells may migrate to injured skin and contribute to a population of cells capable of producing type VII collagen. Preclinical studies demonstrated biochemical improvement and prolonged survival after wild-type bone marrow transplantation in Col7a1-deficient mice [36].

In an early clinical study involving seven children with severe RDEB, surviving recipients showed increased cutaneous type VII collagen deposition and persistence of donor-derived cells in the skin [46]. Subsequent protocols have attempted to improve donor availability and transplant tolerance [47].

However, HSCT carries substantial risks related to conditioning toxicity, infection, graft-versus-host disease and treatment-related mortality. In the initial series, two of seven children died from transplantation-related complications [46]. HSCT should therefore remain restricted to highly selected patients treated within specialised investigational programmes in which its potential systemic benefits can be carefully weighed against its considerable risks [48].

8.3. Protein-Replacement Therapy

Protein-replacement therapy aims to deliver recombinant human type VII collagen directly, avoiding genetic modification of patient cells. Preclinical studies demonstrated that intradermally administered recombinant type VII collagen could localise to the basement membrane zone and promote anchoring-fibril formation [49]. Intravenous administration also resulted in localisation to wounded skin and phenotypic improvement in animal models [50,51].

The recombinant type VII collagen candidate PTR-01 was evaluated in an early clinical study involving patients with RDEB [52]. Infusions were generally well tolerated, and some improvement in wound healing was observed. However, demonstration of consistent formation of mature, functional anchoring fibrils remained challenging.

Important unresolved issues include protein distribution, dosing frequency, immunogenicity and whether systemically administered collagen can be assembled into stable anchoring fibrils within a persistently abnormal cellular and extracellular environment. Paediatric and long-term repeated-dosing data remain limited.

8.4. RNA-Based Therapeutic Strategies

RNA-based treatments provide mutation-specific modulation without permanently altering genomic DNA. Approaches include antisense oligonucleotide-mediated exon skipping, modification of abnormal splicing and pharmacological read-through of premature termination codons.

Antisense oligonucleotides may exclude selected mutation-containing exons from mature COL7A1 messenger RNA, restoring the reading frame and enabling production of a shortened but partially functional type VII collagen protein. Read-through compounds are intended to suppress premature termination codons and permit translation of full-length protein [53].

The principal advantage of these approaches is the absence of permanent genomic modification. However, they are applicable only to defined molecular subgroups and will probably require repeated administration. Their successful implementation will depend on comprehensive genotyping, efficient delivery to affected tissues and demonstration that the amount and function of restored protein are sufficient to produce clinically meaningful benefit.

8.5. Genome Editing

Genome-editing technologies, including CRISPR/Cas9, base editing and prime editing, aim to correct pathogenic variants directly within patient cells, either ex vivo or in situ. Unlike additive gene therapy, these approaches could restore endogenous gene regulation and potentially provide permanent molecular correction.

Preclinical studies have demonstrated correction of COL7A1 variants in keratinocytes and fibroblasts, as well as restoration of type VII collagen in edited skin equivalents and animal models [54,55,56,57]. Exon-deletion strategies have also been developed to remove selected mutation-bearing exons while preserving the reading frame.

Despite their potential, genome-editing approaches remain limited by delivery challenges, variable editing efficiency and concerns regarding off-target changes, unintended chromosomal alterations and long-term genotoxicity. These risks are especially relevant in children, who may live for decades after treatment and whose epidermal stem cells undergo prolonged replication. Extensive preclinical validation and long-term surveillance will therefore be required before routine clinical application.

9. Integrating Emerging Therapies into Care

The available evidence indicates that no single strategy is likely to address the full clinical complexity of EB. Topical pharmacological and gene therapies may improve individual wounds, whereas ex vivo grafts can provide more durable correction in selected areas. Systemic cell-, protein- or RNA-based therapies may eventually complement these approaches by targeting widespread cutaneous or extracutaneous disease.

Future treatment will therefore probably involve personalised combinations selected according to EB subtype, causative variant, residual protein expression, wound phenotype, age and overall disease burden. Such strategies must remain integrated with multidisciplinary supportive care because even successful molecular correction of selected tissues will not immediately reverse established fibrosis, contractures, nutritional impairment or other irreversible complications.

Long-term registries should capture outcomes extending beyond short-term wound closure, including recurrence, pain, pruritus, mobility, growth, nutritional status, school participation, quality of life, caregiver burden and development of cutaneous squamous cell carcinoma. Recent patient-led evidence supports the systematic inclusion of multidimensional patient-reported outcomes alongside conventional clinical endpoints in EB registries [12]. Harmonisation of these outcomes across clinical trials will be essential for determining whether emerging therapies produce meaningful and sustained modification of the natural history of EB.

10. Conclusions

The therapeutic landscape of inherited EB is undergoing a profound transformation. Although multidisciplinary supportive care remains essential, the introduction of pharmacological wound-healing agents, topical gene replacement and ex vivo gene-corrected epidermal grafts has demonstrated that clinically meaningful modification of disease manifestations is achievable. Oleogel-S10, beremagene geperpavec and prademagene zamikeracel represent complementary therapeutic approaches, differing substantially in their mechanisms of action, durability, procedural burden and applicability across EB subtypes.

Nevertheless, currently available therapies remain predominantly directed towards selected cutaneous wounds and cannot fully prevent blister formation, reverse established fibrosis or address the multisystem manifestations of severe EB. Their long-term effects on disability, quality of life and the risk of cutaneous squamous cell carcinoma also remain uncertain. Emerging cell-, protein-, RNA- and genome-editing-based strategies may extend treatment beyond local wound closure by enabling systemic, mutation-specific or potentially permanent correction. However, these approaches continue to face substantial challenges related to delivery, durability, manufacturing complexity, accessibility and long-term safety.

These considerations are particularly important in paediatric patients, for whom early intervention could reduce cumulative tissue damage during growth but may also entail decades of exposure to repeated or genetically modifying treatments. Future clinical trials should therefore incorporate age-appropriate and patient-centred outcomes extending beyond wound closure, including pain, pruritus, mobility, growth, nutritional status, psychosocial well-being, school participation, quality of life and caregiver burden. Long-term registries and harmonised outcome measures will be essential for evaluating treatment durability and identifying delayed adverse effects.

The future management of EB will probably rely on personalised combinations of supportive, pharmacological, molecular and regenerative therapies selected according to genotype, residual protein expression, disease severity and individual clinical needs. Continued collaboration among specialist centres, researchers, regulatory authorities, patients and families will be crucial to ensure that scientific advances translate into safe, durable and accessible treatments. Although a definitive cure remains unavailable, recent progress has established a realistic pathway towards altering the natural history of EB and improving long-term outcomes for affected children and their families.