2024-01-15 15:15:54
Acne is a common skin condition caused by blockage or inflammation of the pilosebaceous follicles. Its appearance can be varied, from whiteheads or blackheads to pustules and nodules that appear mainly on the face, forehead, chest, upper back and shoulders. Although acne is more common among adolescents, it affects people of all ages.
The most severe cases of acne are treated with antibiotics, to eliminate the bacteria that live in the follicles, or with isotretinoin (known as Accutane), a derivative of vitamin A that induces the death of sebocytes (epithelial cells of the skin that produce sebum). However, these treatments can produce serious side effects such as disruption of the homeostasis of the skin microbiome (because they do not selectively eliminate bacteria) or photosensitivity (in the case of antibiotics), or birth defects or extreme peeling of the skin (in the case of antibiotics). case of isotretinoin).
An international investigation led by the Translational Synthetic Biology Laboratory of the Department of Medicine and Life Sciences (MELIS) of the Pompeu Fabra University in Barcelona has managed to efficiently edit (modify) Cutibacterium acnes (a type of skin bacteria). so that it produces and secretes a therapeutic molecule suitable for treating acne symptoms. The engineered bacteria have been tested on skin cell lines and their administration has been validated in mice. This finding opens the door to expanding the avenue of engineering non-editable bacteria to treat skin disorders and other diseases through living therapies.
The research team is completed by scientists from the Bellvitge Biomedical Research Institute (IDIBELL), the University of Barcelona, the Protein Technology Service of the Center for Genomic Regulation, Phenocell SAS, Medizinische Hochschule Brandenburg Theodor Fontane and the Universities of Aarhus and Lund .
The results of the study show that the researchers have managed to edit the genome of the aforementioned skin bacteria, Cutibacterium acnes, so that it produces and secretes the NGAL protein, known to be a mediator of the anti-acne drug, isotretinoin, which has been shown reduce sebum by inducing the death of sebocytes.
“We have developed a topical therapy with a targeted approach, using what nature already has. We have engineered a bacteria that lives on the skin and produces what our skin needs. In this case, we have focused on treating acne, but This platform can be extended to many other indications,” says Nastassia Knödlseder, first author of the study.
Broaden the path of bacterial engineering
“Until now, C.acnes was considered an untreatable bacteria. It was incredibly difficult to introduce DNA and get it to produce or secrete proteins from an element inserted into its genome,” explains Knödlseder, who is a postdoctoral fellow in the Synthetic Biology Laboratory of the UPF.
However, as this bacteria seems to be an attractive synthetic biology chassis to treat skin diseases, given that it resides inside the hair follicles – practically where sebum is released -; its importance for skin homeostasis; Its close contact with relevant therapeutic targets and the fact that it has been shown to successfully engraft when applied to human skin, led researchers to insist on editing the genome of this non-manipulating bacterium.
To edit the C.acnes genome, the research team led by Marc Güell has focused on improving the supply of DNA to the cell, the stability of DNA within the cell and gene expression. In addition, they have taken regulatory measures into account by developing a biocontainment strategy to avoid the use of elements that raise regulatory concerns. For this reason, they have avoided using mobile genetic elements, plasmids or antibiotic resistance. Thus, the resulting synthetic bacteria has safety characteristics that make its use in “real life” possible and its consideration for future human therapies.
The new synthetic bacteria is capable of secreting and producing NGAL to modulate sebum production in cell lines. And, when applied to the skin of mice – the only animal model capable of testing engineered bacteria to date – it engrafts, lives and produces the protein of interest. However, mouse skin is not comparable to that of humans. It has more hair, is looser, has less lipids and a different sweating mechanism. That is why an alternative model is necessary, which better represents human skin, such as 3D skin models.
Artistic recreation of genetically manipulated bacteria. (Illustration: Amazings/NCYT)
The route to therapy
“We have developed a technological platform that opens the door to editing any bacteria to treat multiple diseases. We are now focused on using C.acnes to treat acne, but we can offer genetic circuits to create smart microbes for applications related to skin detection or immune modulation,” says Marc Güell, who led the research.
Following the same strategy, this line of research will continue within the framework of the European project “SkinDev”, in which scientists from the Synthetic Biology laboratory and their partners will edit the C.acnes bacteria to treat atopic dermatitis, a chronic inflammatory skin disease characterized for dry skin, eczema and severe irritation that especially affects young children.
Although any living therapeutic strategy must be validated individually, the researchers are optimistic about applying these intelligent microbes to humans because unmanipulated C.acnes has already been tested on the skin of patients showing safety and efficacy.
The study is titled “Delivery of a sebum modulator by an engineered skin microbe in mice.” And it has been published in the academic journal Nature Biotechnology. (Source: UPF)
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