Allogeneic Haematopoietic Cell Transplantation for Epidermolysis Bullosa: the Dutch Experience

Gostyńska, Katarzyna B.; Yenamandra, Vamsi K; Lindemans, Caroline A.; Duipmans, José C.; Gostyński, Antoni; Jonkman, Marcel F.; Boelens, Jaap-Jan

doi:10.2340/00015555-3097

Cited by 11 publications

(8 citation statements)

References 15 publications

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“…In the last decade HSCT has been considered for EB treatment, 17 although the mechanisms underlying the benefits of this intervention have yet to be elucidated and BM ablation in patients with severe skin fragility pathology can be lethal. 38 Recently, Ebens et al 12 showed that HSCT followed by MSC infusions could ameliorate the RDEB phenotype. MSCs can potentially express C7 and have an immunoregulatory role in wound healing, which could contribute to decreased inflammation and dermal-epidermal adhesion restoration.…”

Section: Discussionmentioning

confidence: 99%

Correction of recessive dystrophic epidermolysis bullosa by homology-directed repair-mediated genome editing

et al. 2021

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Genome-editing technologies that enable the introduction of precise changes in DNA sequences have the potential to lead to a new class of treatments for genetic diseases. Epidermolysis bullosa (EB) is a group of rare genetic disorders characterized by extreme skin fragility. The recessive dystrophic subtype of EB (RDEB), which has one of the most severe phenotypes, is caused by mutations in COL7A1. In this study, we report a gene-editing approach for ex vivo homology-directed repair (HDR)-based gene correction that uses the CRISPR-Cas9 system delivered as a ribonucleoprotein (RNP) complex in combination with donor DNA templates delivered by adeno-associated viral vectors (AAVs). We demonstrate sufficient mutation correction frequencies to achieve therapeutic benefit in primary RDEB keratinocytes containing different COL7A1 mutations as well as efficient HDR-mediated COL7A1 modification in healthy cord blood-derived CD34 + cells and mesenchymal stem cells (MSCs). These results are a proof of concept for HDR-mediated gene correction in different cell types with therapeutic potential for RDEB.

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Section: Discussionmentioning

confidence: 99%

Correction of recessive dystrophic epidermolysis bullosa by homology-directed repair-mediated genome editing

et al. 2021

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“…Seven RDEB children underwent myeloablative chemotherapy and allogeneic stem cell transplantation: one died before transplantation and another from later graft rejection and infection, but the other five had long-term donor cell expression, with new C7 at DEJ [86]. To lessen morbidity and mortality, conditioning regimens with reduced intensity were then introduced [87,88]. Precisely how BMT works in RDEB, however, is uncertain since some patients also showed clinical improvement in the absence of any new C7.…”

Section: Bone Marrow Transplantationmentioning

confidence: 99%

Investigational Treatments for Epidermolysis Bullosa

et al. 2021

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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.

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“…Following this experience, a trial was opened in Netherlands and two patients were treated with UCBT. Unfortunately, they both died of treatment-related complications and the trial was prematurely closed (Gostynska et al, 2019). Therefore, further data need to be collected before any definitive recommendation can be made in this field.…”

Section: Novel Indicationsmentioning

confidence: 99%

Current status of umbilical cord blood transplantation in children

2019

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Summary The first umbilical cord blood (UCB) transplantation was performed 30 years ago. UCB transplantation (UCBT) is now widely used in children with malignant and non‐malignant disorders who lack a matched family donor. UCBT affords a lower incidence of graft‐versus‐host disease compared to alternative stem cell sources, but also presents a slower immune recovery and a high risk of infections if serotherapy is not omitted or targeted within the conditioning regimen. The selection of UCB units with high cell content and good human leucocyte antigen match is essential to improve the outcome. Techniques, such as double UCBT, ex vivo stem cell expansion and intra‐bone injection of UCB, have improved cord blood engraftment, but clinical benefit remains to be demonstrated. Cell therapies derived from UCB are under evaluation as potential novel strategies to reduce relapse and viral infections following transplantation. In recent years, improvements within haploidentical transplantation have reduced the overall use of UCBT as an alternative stem cell source; however, each may have its relative merits and disadvantages and tailored use of these alternative stem cell sources may be the optimal approach.

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Allogeneic Haematopoietic Cell Transplantation for Epidermolysis Bullosa: the Dutch Experience

Cited by 11 publications

References 15 publications

Correction of recessive dystrophic epidermolysis bullosa by homology-directed repair-mediated genome editing

Correction of recessive dystrophic epidermolysis bullosa by homology-directed repair-mediated genome editing

Investigational Treatments for Epidermolysis Bullosa

Current status of umbilical cord blood transplantation in children

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