FP14 Recombinant protein therapy for the treatment of junctional epidermolysis bullosa
Thomas Kirk, Emanuel Rognoni, Matthew CaleyAbstract
Introduction and aims
Junctional epidermolysis bullosa (JEB) is a rare genetic skin disorder leading to severe skin fragility from birth. It is caused by mutations in genes encoding the skin basement membrane proteins, Laminin 332, type XVII collagen or the basement membrane binding integrin α6β4, which anchor the epidermis to the dermis. JEB is characterized by widespread blistering of the skin and mucous membranes. The most severe form, JEB generalized severe, is caused by loss-of-function mutations in one of the chains of the trimeric protein Laminin 332. Babies diagnosed with this form of JEB generally do not survive beyond their first birthday. Patients suffer from failure to thrive, poor wound healing, anaemia, respiratory complications, and infections. The aim of this project is to explore the possibility of delivering recombinant laminin 332 (rLM332) to JEB skin to improve skin function.
Methods
We used a tamoxifen inducible mouse model of JEB (Lama3flox/floxK14CreERT), in which the Lama3 gene is specifically deleted in K14 expressing cells. JEB mice develop progressive blistering of skin and mucosa and exhibit reduced weight gain, mirroring the human disease. We examined the potential of rLM332 to treat JEB, exploring topical and subcutaneous injection and the impact on wound healing and disease severity biomarkers.
Results
We found both subcutaneous injection and topical application of rLM332 results in localization of the protein to the basement membrane. We observed improved wound healing, reduced blistering, improved basement membrane type VII collagen localization, and changes to the immune environment with rLM332 treatment. These changes persist at least 10 days following the final application.
Conclusions
Recombinant protein therapy presents a promising avenue for the treatment of JEB in patients, with topical application a potential noninvasive method of delivery in babies with extremely fragile skin. Murine experiments indicate durable improvements in skin health and accelerated wound healing.