Skin diseases affect millions of people worldwide but are often poorly addressed, due to lack of resources, expensive or inefficient treatments, or their non-urgent, non-life-threatening nature. Atopic dermatitis (AD) alone affects 7-10% of adults (and up to 25% of children), making it the most common chronic inflammatory skin disease. While non-fatal (and sometimes perceived as relatively benign), AD severely affects patients’ quality of life. The characteristic itch/pruritus can lead to sleep deprivation and adverse psychosocial effects due to the high visibility of the lesions, including attention deficit, anxiety and depression. Besides, AD patients show a propensity towards skin infections, mainly by Staphylococcus aureus and herpes. The economic burden of AD amounts to $5.3 billion only in the US, and current treatments are either highly expensive ($37,000/patient/year for Dupilumab) or linked to important adverse effects, such as skin thinning linked to topical corticosteroids or immunodeficiency linked to systemic immunosuppressants.
This project aimed at producing the basic tools and knowledge for the future use of engineered human skin microbiome for diagnostics and treatment of skin diseases in general and of AD in particular. While the modification of the gut microbiome for medical uses is exponentially growing and starting to unfold its potential, the modification of the skin microbiome is clearly lagging behind. Cutibacterium acnes (formerly Propionibacterium acnes) an inhabitant of the pilosebaceous unit and the most abundant skin bacterium; a Gram-positive anaerobe contributing to skin homeostasis. C. acnes constitutes an ideal framework for the development of living biotherapeutics for several reasons, including its high abundance and low turnover, its relevance in both health and disease, its natural biocontainment within the pilosebaceous unit, and its engraftment capabilities when transferred to a recipient individual.
Despite its huge potential, there existed important limitations to the modification of C. acnes that prevented further advancement. For example, almost no tool was available for C. acnes engineering, and successful delivery of DNA into this bacterium had been scarcely reported. The first goal of the project was therefore to improve the transformability of C. acnes and to develop tools for its programming as a living medical device. Next, I aimed to use this toolset to develop C. acnes strains able to sense inflammation and respond to it by releasing anti-inflammatory molecules. Finally, I sought to validate the engraftment and activity of the engineered strains in a mouse model of atopic dermatitis.
The research performed has accomplished most of the initial objectives, and notably those that serve as basis for future development of the technology. We are now able to routinely deliver exogenous DNA into C. acnes, and have developed the molecular biology tools to engineer these bacteria for medical (or other) purposes. Some of our engineer strains secrete active anti-inflammatory proteins, and we have demonstrated successful engraftment in model mice. We continue developing inflammation sensors, and the in vivo validation of a strain that senses inflammation and responds to it will follow.
Other than research, during the course of the fellowship I have continued to develop transversal skills of high relevance for my career development, such as leadership and mentoring (courses, Master student or iGEM team (>10 student) supervision), teaching (undergraduates), or communication (talks, outreach).
