Scientists ‘Have Developed A Topical Therapy’ That Can Help Regulate Sebum Production and Treat Acne – a Common Skin Condition.
A team led by the Translational Synthetic Biology Laboratory of the Department of Medicine and Life Sciences (MELIS) at Pompeu Fabra University has successfully engineered Cutibacterium acnes, a type of skin bacterium, to efficiently produce and release a therapeutic molecule for the treatment of acne symptoms.
The engineered bacterium has undergone validation in skin cell lines, and its delivery has been confirmed in mouse models. This breakthrough offers a promising avenue for manipulating non-responsive bacteria to address skin conditions and other diseases through the use of living therapeutics.
Collaborating with scientists from the Bellvitge Biomedical Research Institute (Idibell), the University of Barcelona, the Protein Technologies Facility of the Centre for Genomic Regulation, Phenocell SAS, Medizinische Hochschule Brandenburg Theodor Fontane, Lund University, and Aarhus University, the research showcases a significant advancement in the field of dermatology.
Acne, a common skin condition resulting from pilosebaceous follicle blockage or inflammation, can manifest in various forms, including whiteheads, blackheads, pustules, and nodules, typically appearing on the face, forehead, chest, upper back, and shoulders. While commonly associated with adolescents, acne can affect individuals of all ages.
Current severe acne treatments involve antibiotics or isotretinoin (Accutane), a vitamin A derivative that induces sebocyte death. However, these approaches may lead to adverse effects such as disruption of skin microbiome homeostasis, photosensitivity, birth defects, or extreme skin scaling.
Published in Nature Biotechnology, the study demonstrates successful genome editing of Cutibacterium acnes to produce the NGAL protein, a mediator of the acne drug isotretinoin. NGAL has been proven to reduce sebum production by inducing sebocyte death.
Nastassia Knödlseder, the first author of the study, emphasizes, “We have developed a topical therapy with a targeted approach, using what nature already has. We engineered a bacterium that lives in the skin and make it produce what our skin needs.”
“Until now, C. acnes was considered an intractable bacterium. It was incredibly difficult to introduce DNA and get proteins produced or secreted from an element inserted into its genome,” as explained by Knödlseder.
However, C. acnes stands out as an appealing synthetic biology platform for addressing skin diseases, primarily due to its specialized habitat within hair follicles, precisely where sebum is released. Its significance for skin homeostasis, proximity to pertinent therapeutic targets, and demonstrated successful engraftment on human skin underscore its potential.
Given these advantages, the research team, led by Marc Güell, was determined to overcome the challenges of editing the genome of this previously non-engineerable bacterium.
To accomplish genome editing of C. acnes, the team concentrated on enhancing DNA delivery to the cell, maintaining DNA stability inside the cell, and optimizing gene expression. They implemented regulatory measures, devising a biocontainment strategy to eliminate elements raising regulatory concerns, such as mobile genetic elements, plasmids, or antibiotic resistance. Consequently, the resulting synthetic bacterium incorporates safety features essential for practical application in real-life scenarios and consideration for future human therapeutics.
The synthetic C. acnes variant has demonstrated the ability to secrete and produce NGAL, effectively modulating sebum production in cell lines. When applied to the skin of mice—the sole animal model currently suitable for testing engineered bacteria—they successfully engraft, thrive, and produce the desired protein.
Yet, mouse skin differs significantly from human skin. It possesses higher hair density, greater laxity, lower lipid content, and a distinct sweat mechanism. Therefore, there arises a crucial requirement for an alternative model that more accurately mirrors human skin, with 3D skin models emerging as a promising solution.
“We have developed a technology platform that opens the door to editing any bacteria to treat multiple diseases. We are now focused in using C. acnes to treat acne but we can deliver genetic circuits to create smart microbes for applications related to skin sensing, or immune modulation,” points out lead author Marc Güell.
This research line will continue using the same approach under the European Project “SkinDev,” in which researchers from the Translational Synthetic Biology lab and its partners will engineer C. acnes to treat atopic dermatitis, a chronic inflammatory condition of the skin that is characterized by severe irritation, eczema, and dry skin and is particularly common in young children.
While each living therapies approach has to be independently confirmed, the researchers express hope about using these intelligent bacteria on people since non-engineered C. acnes has been successfully and safely tested on patient skin.
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