Advances on potential therapeutic options for epidermolysis bullosa

ABSTRACT

Introduction: Epidermolysis bullosa is a severe genodermatosis in which pain and wound management dominate patients’ lives leaving a high demand for more effective treatments. At present, gene therapy is the only treatment with the potential to cure inherited diseases. A small number of individuals with junctional and dystrophic forms of epidermolysis bullosa have received gene replacement therapies involving ex vivo viral transduction of intact transgenes into skin stem cells followed by autologous grafting of corrected epidermal sheets. Corrected stem cells ensure permanent regeneration of stable skin at the graft sites.

Areas covered: Alternative therapeutic options are either RNA-based or involve the latest preclinical developments in the area of gene editing using designer nucleases such as TALEN or CRISPR/Cas9, which enable precise targeting of any desired locus and a potential traceless repair of mutations. Due to low targeting efficiencies and safety considerations regarding off-target effects, research in this area focuses on ex vivo approaches involving selection of correctly modified keratinocyte clones.

Expert opinion: Although there is currently no single optimal therapy for epidermolysis bullosa, cell and gene therapy technologies are advancing rapidly holding great potential for modifying disease severity and improving quality of life for people living with this devastating disease.

KEYWORDS:

• CRISPR/Cas9
• epidermolysis bullosa
• gene editing
• gene therapy
• keratinocytes
• RNA trans-splicing
• stem cells
• TALEN

Declaration of interest

LDR and MDL are partially funded by Regione Emilia-Romagna, Asse 1 POR-FESR 2007–13. MDL is a founder and member of the Board of Directors of Holostem Terapie Avanzate (HTA), s.r.l, Modena, Italy. JR, UK, and JWB are partially funded by DEBRA Austria. JWB is inventor on US (US8735366) and European (EP2320952) patent ‘Improved pre-mRNA trans-splicing molecules (RTM) and their uses’. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Article highlights

• Gene replacement therapies represent a promising and safe treatment option for junctional epidermolysis bullosa.

• Initial phase I/II clinical trials for junctional epidermolysis bullosa demonstrate evidence that local transplantations of transgenic epidermal sheets can generate a functional epidermis, leading to permanent and safe correction without serious side effects so far.

• Epidermal stem cells (EpSCs) are easily grown ex vivo without losing their stemness and represent a suitable source of autologous adult stem cells that can be used for EB gene therapy.

• In addition to EpSCs, iPSCs derived from EB fibroblasts, keratinocytes or possibly other cell types may provide an alternative target for gene therapy in EB provided that safety issues can be tackled in the future.

• Precise site-specific gene targeting and editing can be achieved using designer nucleases.

• Potentially safe treatment options for EB at RNA level include RNA modulation via RNA trans-splicing or exon skipping via antisense oligonucleotides.

This box summarizes key points contained in the article.

Additional information

Funding

DEBRA Austria and Regione Emilia-Romagna (Asse 1 POR-FESR 2007–13).