In 1996, Paul Khavari and his team published the first studies on the delivery of the transglutaminase 1 gene into cells of patients using retroviruses thereby pioneering modern cutaneous gene therapy. Congenital ichthyosis is a group of rare genodermatose that usually manifests as a severe keratinization disorder. Since the regulatory approval of the first-ever gene therapy, Glybera, in 2012, many others have set foot in the realm of gene-based therapeutics to cure diseases previously known to be untreatable. Although now withdrawn, success stories exist satisfying the potential of the field. Some of the most promising cases have been seen in sickle-cell disease, beta thalassemia, and spinal muscular atrophy. Despite the advancements in the past decade, little attention has been paid to the applications in the skin and its diseases [1, 2].
Why the skin?
But what makes the skin a fitting target for gene-based approaches? Firstly, the skin is the largest organ and is very accessible and superficial. This allows the organ to be easily manipulated and observed for adverse effects. The fact that the restoration of only 10% of the normal gene function radically alleviates the skin condition is a low threshold; and is potentially achievable amidst the challenges existing in current gene delivery methods .
What is gene therapy?
Gene therapy is defined as a therapeutic method that uses a vector to deliver nucleic acid into cells to combat a pathological process by altering the gene expression The current toolset includes gene augmentation, gene repair/editing, and RNA-based therapies for a multitude of human diseases. Limited to the preclinical settings, some of the candidate skin diseases under study are Epidermolysis Bullosa (EB), Sjogren-Larsson syndrome (SLS), ichthyosis, xeroderma pigmentosum, and so on. Apart from genetic diseases, chronic wounds, and skin cancer can be treated with the therapy. Patients suffering from untreatable, often rare, skin disorders will be benefitted once researchers make headway in the hurdles associated with the barrier properties of the skin .
Barriers to success
The one-of-a-kind structural organization of the skin limits the absorption of biomolecules hampering the efficient delivery of nucleic acid payloads. As a matter of fact, the human skin permits absorptions of moderately lipophilic molecules of molecular weight less than or equal to 800 Daltons. The gene being negatively charged and hydrophilic poses challenges in getting across the layers .
Generally, the delivery strategy can be divided into viral and non-viral-based systems such as lipid-based or polymeric nanoparticles, and physical methods like electroporation and cellular sonication. Optimization of administration techniques and perhaps vector design should pave the way for making the therapy available globally. With many of the target skin diseases under orphan designations, it is to be noted that the efficacy rate of the treatment, commercial success, and accessibility are too involved in the interplay.
Daley, J. (2021) Four success stories in gene therapy, Scientific American. Scientific American. Available at: https://www.scientificamerican.com/article/four-success-stories-in-gene-therapy/ (Accessed: January 12, 2023).
Warner, E. (2022) Goodbye Glybera! the world's first gene therapy will be withdrawn, Labiotech.eu. Available at: https://www.labiotech.eu/trends-news/uniqure-glybera-marketing-withdrawn/ (Accessed: January 12, 2023).
Gorell, E. et al. (2014) “Gene therapy for skin diseases,” Cold Spring Harbor Perspectives in Medicine, 4(4). Available at: https://doi.org/10.1101/cshperspect.a015149.
Sarkar, S., Sarkar, T. and Gangopadhyay, D.N. (2020) “Gene therapy and its application in dermatology,” Indian Journal of Dermatology, 65(5), p. 341. Available at: https://doi.org/10.4103/ijd.ijd_323_20.
Ain, Q.U. et al. (2021) “Gene delivery to the skin – how far have we come?,” Trends in Biotechnology, 39(5), pp. 474–487. Available at: https://doi.org/10.1016/j.tibtech.2020.07.012.