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Promises and challenges of gene therapy for congenital dermatoses

Gene therapy for genodermatoses is a rapidly evolving field of research with the potential to greatly improve patient quality of life. Treatment costs and navigating regulatory bodies are two challenges to the wider adoption of these treatments that technology may help overcome.


These topics were discussed during a presentation by Sarah Hedtrich, PhD, at the Inaugural Canadian Genodermatoses Network Meeting in Toronto on April 5, 2024.


Dr. Hedtrich is an Associate Professor in the Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver.


The meeting was a one-day event hosted by The Hospital for Sick Children (SickKids) that brought together a range of stakeholders to improve the lives of Canadian patients with rare genetic skin diseases.


In her presentation, Dr. Hedtrich provided an overview of gene editing therapy for genodermatoses, including the benefit CRISPR-Cas9 technology has provided to the field.

Dr. Hedtrich and her colleagues are working to develop topically applicable gene therapy for genodermatosis patients, with a particular focus on treating congenital ichthyosis. She said she believes the technologies she and her team are developing will be easily adapted to target other genodermatoses, such as epidermolysis bullosa.


In contrast with research that has explored modifying the genes of cells extracted from a patient and then culturing the cells into a skin graft, Dr. Hedtrich’s lab is working on simplifying the logistics by finding ways to modify the genes of skin stem cells in situ.


Other researchers have had some success in this area—Dr. Hedtrich noted that in May 2023, the U.S. Food and Drug Administration approved the first topical gene therapy for the treatment of wounds in patients with dystrophic epidermolysis bullosa. This product, marketed under the name Vyjuvek, uses a viral vector to deliver the gene-editing factors into the skin.


“The problem with those viral vectors is that although they are very efficient, they are very difficult to produce and it costs a lot of money,” said Dr. Hedtrich.


Her team is working to develop ways of using non-viral vectors, specifically lipid nanoparticles, to deliver gene-editing payloads into the skin. Because the skin barrier, even in diseased skin, impairs the delivery of large molecules, Dr. Hedtrich and her colleagues have been trying laser microporation with depth guidance supported by confocal microscopy to ensure the nanoparticles can reach deep enough in the skin to impact stem cells while not going so deep as to risk systemic exposure.


In three-dimensional human skin models, using this approach she and her colleagues have been achieving successful gene editing rates between 5% and 12%.


“In the context of congenital ichthyosis there is some data that suggests that if you only correct five to 10 per cent of the disease-causing mutations this suffices to offset the most severe symptoms, and so this is our minimal threshold that we are trying to reach,” she said.

However, there are significant challenges in assessing efficacy and getting approval for human trials of gene editing treatments, Dr. Hedtrich said.


There are no animal models for congenital ichthyosis, so Dr. Hedtrich and her team had to negotiate with regulatory authorities and demonstrate their skin models worked to have them accepted as valid efficacy tests. Safety tests are being conducted in mouse models.

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