Leading edge: emerging drug, cell, and gene therapies for junctional epidermolysis bullosa

ABSTRACT

Introduction

Junctional epidermolysis bullosa (JEB) is a rare inherited genetic disorder with limited treatments beyond palliative care. A major hallmark of JEB is skin blistering caused by functional loss or complete absence of major structural proteins of the skin. Impaired wound healing in patients with JEB gives rise to chronic cutaneous ulcers that require daily care. Wound care and infection control are the current standard of care for this patient population.

Areas covered

This review covers research and clinical implementation of emerging drug, cell, and gene therapies for JEB. Current clinical trials use topical drug delivery to manipulate the inflammation and re-epithelialization phases of wound healing or promote premature stop codon readthrough to accelerate chronic wound closure. Allogeneic cell therapies for JEB have been largely unsuccessful, with autologous skin grafting emerging as a reliable method of resolving the cutaneous manifestations of JEB. Genetic correction and transplant of autologous keratinocytes have demonstrated persistent amelioration of chronic wounds in a subset of patients.

Expert Opinion

Emerging therapies address the cutaneous symptoms of JEB but are unable to attend to systemic manifestations of the disease. Investigations into the molecular mechanism(s) underpinning the failure of systemic allogeneic cell therapies are necessary to expand the range of effective JEB therapies.

KEYWORDS:

• Basement membrane zone
• cell therapy
• clinical trials
• drug therapy
• extracellular matrix
• gene therapy
• hematopoietic cell transplant
• junctional epidermolysis bullosa
• keratinocytes
• wound healing

Article Highlights

• Junctional epidermolysis bullosa is a rare, inherited genetic disease that has no cure.

• Drug therapies in clinical trials may provide therapeutic benefit by influencing phases in cutaneous wound-healing (Oleogel-S10 and RGN-137) or promoting readthrough of premature stop codons to generate full-length protein (gentamicin).

• Although systemic allogeneic cell therapies have demonstrated clinical benefits in patients with RDEB, these approaches have been largely unsuccessful in patients with β3-deficient JEB.

• Autologous skin grafting for the closure of chronic wounds could be achieved if patients with JEB have areas of revertant mosaicism, in which somatic mutational events correct genetic defects or by ex vivo genetic correction and subsequent autologous transplant.

• Current therapies are limited to the cutaneous symptoms of JEB, while systemic manifestations have demonstrated minimal improvement.

Declaration of Interest

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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This research was supported by the National Institutes of Health’s National Center for Advancing Translational Sciences, grants KL2TR002492 and UL1TR002494. The content is the sole responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health’s National Center for Advancing Translational Sciences.