An ex vivo RNA trans-splicing strategy to correct human generalized severe epidermolysis bullosa simplex

British Journal of Dermatology, 2019 · DOI: 10.1111/bjd.17075 · Published: January 1, 2019

Simple Explanation

This research focuses on a genetic skin disease called generalized severe epidermolysis bullosa simplex (EBS-gen sev). EBS-gen sev is caused by mutations in the KRT5 or KRT14 genes, which are important for the structure of skin cells. The study explores a new way to fix this genetic problem using RNA trans-splicing. This method uses a special RNA molecule to replace the mutated part of the gene with a healthy version. The corrected skin cells were then used to create skin equivalents, which were grafted onto mice. The results showed that the corrected skin was stable and blister-free, suggesting that this approach could be a potential treatment for EBS-gen sev.

Study Duration

8 weeks

Participants

EBS patient-derived keratinocyte line, nude mice

Evidence Level

Not specified

Key Findings

1
Transplanted skin equivalents generated from trans-splicing-corrected patient keratinocytes showed a stable and blister-free epidermis.
2
KRT14 correction disrupted EBS-gen sev-associated proinﬂammatory signalling, as shown at the mRNA and protein levels.
3
Reduction in the expression of the mutated allele in comparison with the wild-type allele upon trans-splicing-mediated correction results in downregulation of IL-1b-mediated JNK-signalling.

Research Summary

This study presents an ex vivo RNA trans-splicing-based therapeutic approach to correct the phenotype of generalized severe epidermolysis bullosa simplex (EBS-gen sev). The researchers stably transduced a therapeutic RNA trans-splicing molecule containing wild-type exons 1–7 into an EBS patient-derived keratinocyte line, confirming trans-splicing via various methods. Transplanted skin equivalents generated from corrected keratinocytes showed a stable and blister-free epidermis, disrupting EBS-gen sev-associated proinﬂammatory signaling and highlighting the effect of KRT14 correction on the EBS pathomechanism.

Practical Implications

Potential Therapy for EBS-gen sev

The study demonstrates the feasibility of using spliceosome-mediated RNA trans-splicing to generate a stable and blister-free epidermis in vivo, suggesting a potential therapeutic approach for EBS-gen sev.

Treatment for Inherited Genodermatoses

Combined with pre-existing ex vivo gene therapeutic methods, this might be a valid option for future treatments of dominantly inherited genodermatoses.

Reduction of Keratin 14 Overexpression

SMaRT can reduce keratin 14 overexpression and to phenotypically correct patient keratinocytes, indicating the potential high impact of this treatment in EBS.

Study Limitations

1
Stable viral integration is required, accompanied by risks such as insertional mutagenesis and generation of DNA rearrangements during the viral packaging.
2
Effective and precise delivery of RNA molecules into the skin, and in particular into keratinocyte stem cells, remains a major hurdle.
3
Corrective effect is reversible when using nonviral vectors for in vivo skin delivery, requiring a continuous repetition of the treatment.

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