Original article
Successful therapeutic transplantation of revertant skin in epidermolysis bullosa

https://doi.org/10.1016/j.jaad.2013.08.052Get rights and content

Background

Epidermolysis bullosa (EB) is a group of genetic blistering diseases. Despite many efforts, treatment for EB remains symptomatic. Revertant mosaicism, coexistence of cells carrying disease-causing mutations with cells in which the inherited mutation is genetically corrected by a spontaneous genetic event (revertant cells) in 1 individual, can be found in EB. The naturally corrected revertant keratinocytes provide an opportunity for autologous cell therapy.

Objective

We sought to locally treat EB by transplantation of revertant skin.

Methods

Persistent ulcers in a patient with non-Herlitz junctional EB caused by mutations in the LAMB3 gene were treated by transplantation of split-thickness biopsy specimens from one of his revertant patches.

Results

All transplanted biopsy specimens were accepted and complete re-epithelialization occurred within 14 days. During 18 months of follow-up, the patient never experienced blisters or wounds in the grafted area, nor in the healed donor site. Immunofluorescence and DNA sequencing showed that acceptor sites healed with transplanted revertant keratinocytes.

Limitations

Punch grafting allows only limited expansion of revertant skin.

Conclusions

We demonstrate that phenotypical and genotypical correction of skin in patients with revertant mosaicism by expansion of revertant skin might be a promising therapeutic option for cutaneous manifestations of EB.

Section snippets

Patient and intervention

Patient 029-01, a 69-year-old man with non-Herlitz junctional EB caused by a homozygous splice-site mutation in the LAMB3 gene (c.628G>A) had been confined to a wheelchair since 1993 after transfemoral left leg amputation as a result of cutaneus squamous cell carcinoma.15 He presented with 7 persistent (>1 year) and painful ulcers: 6 on the lower aspect of his back (Fig 1, B) and 1 on his right foot. The total area of the ulcers was 7 cm2 and no signs of malignancy were present. On the

Results

Inspection took place 5 and 7 days after the procedure during which adequate wound healing and no signs of infection were observed. All 73 transplanted punch biopsy specimens were accepted in the grafted area and complete re-epithelialization occurred within 14 days (Fig 1, D and E). Interestingly, 21 days after the procedure a blister appeared next to one of the treated ulcers. The blister did not spread into the transplanted area (Fig 1, D), suggesting that the healthy phenotype had been

Discussion

Transplantation of revertant skin, and therefore expansion of healthy, disease-free skin, can highly improve quality of life in patients with EB. Earlier attempts, focused on cultured skin equivalents, were not successful because of an insufficient amount of revertant cells in the grafts (<3%).14 In this report we show that both donor and acceptor sites healed with revertant epidermis and expressed amounts of laminin-332 comparable with normal-appearing human skin. Moreover, by tracing the

References (16)

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    Notably, HR is the only reported reversion mechanism in these disorders; all investigated revertant epidermis samples showed characteristic long-tract LOH that originated from regions centromeric to pathogenic mutations and extended to the telomere [16–18,39,42]. To date, some therapeutic attempts using revertant skin patches or keratinocytes, including successful therapeutic transplantation of revertant skin for refractory skin ulcers in a patient with non-Herlitz junctional EB [51] and successful establishment of mutation-free induced pluripotent stem cells generated from revertant junctional or recessive dystrophic EB keratinocytes [52,53], have been reported. Elucidating the molecular basis of revertant mosaicism—especially how mutant proteins induce long-tract LOH—could expand the possibility of manipulating HR to induce the reversion of disease-causing mutations, and potentially benefit patients with IWC and LK, as well as other currently intractable genetic diseases.

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    Very few attempts to treat EB ulcers with RM have been reported. Gostyński and colleagues successfully performed full-thickness skin grafting from revertant areas to refractory ulcers in a patient with JEB (Gostyński et al., 2014). CEA treatment involving RM was performed by the same group for a patient with JEB, but the clinical effect was reported to be unsatisfactory (Gostyński et al., 2009).

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Funded by the Dutch Butterfly Child Foundation (Stichting Vlinderkind).

Conflicts of interest: None declared.

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