Our research Completed projects Uitto 1 (2017) Novel approaches for read-through of nonsense mutations in COL7A1 Contents: Project information Lay summary Investigator: Professor Jouni Uitto Institution: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, USA Grant: $307,802 (01/10/2014 - 30/09/2017) Lay summary The outermost layer of skin, the epidermis, is connected to the underlying layer, the dermis, by a variety of proteins; some of the most important ones belong to the family of collagens. In Dystrophic Epidermolysis Bullosa (DEB), there is a genetic fault (a mistake) in the structure of type VII collagen, and specifically, reduced, altered or absent type VII collagen is unable to join the epidermis and dermis together as firmly as it should, with the result that people with DEB have fragile skin that is prone to blistering. The gene that controls the synthesis of type VII collagen in skin cells is called COL7A1. Approximately 10% of the mutations (mistakes) in COL7A1 result in a shortened type VII collagen protein being produced, that cannot function properly. The information that is contained in genes is ‘read’ by other molecules; this then directs the assembly of the necessary building blocks for the protein and ensures they are linked together in the correct order. Mutated COL7A1 has a ‘stop’ signal in the gene, that should not be there, with the result that the reading process and the assembly of the protein stops short. There are now novel compounds that when introduced into the cell allow this stop signal to be ignored and normal length type VII collagen can be synthesized (in spite of the mutation or mistake in the gene). This group has been investigating Amlexanox; an FDA (United States Food and Drug Administration) approved drug (for other indications) for its ability to recover the missing protein in cells isolated from recessive dystrophic epidermolysis bullosa (RDEB) patients with a certain type of COL7A1 mutation, called a premature termination codon (PTC). This study shows that Amlexanox helps to produce full length protein (type VII collagen), and the results suggest that this protein is functional (it works properly in the skin). In other words, the protein induced by Amlexanox treatment will likely be beneficial to patients with a PTC in their COL7A1. The amount of type VII collagen that is induced by Amlexanox treatment in RDEB patient cells is relatively low compared to non-RDEB controls, but the results are encouraging given that type VII collagen has a high stability and it can potentially accumulate in the patients’ skin during treatment. Protein stability and long term treatment of patient cells is currently being explored. This group is optimistic about the potential benefit of Amlexanox for treatment of RDEB patients since this drug is currently in clinical use for other diseases, it is well tolerated, and its effects in the body have been established. Furthermore, the drug has anti-inflammatory properties which could further benefit patients. This research is also studying the mechanism by which Amlexanox induces type VII collagen production and whether it would be possible to predict which patients would benefit from this approach, so the treatment could be offered to those who need it most. What is important about this research? “DEBRA funding will allow the application of this treatment modality, if shown to be successful in our preclinical studies, to be directly applicable to patient care." Investigator Biography Jouni Uitto, MD, PhD, has been Professor and Chair of the Department of Dermatology and Cutaneous Biology, and Director of the Jefferson Institute of Molecular Medicine at Thomas Jefferson University, Philadelphia, since 1986. His primary research interests revolve around heritable skin diseases, including dystrophic epidermolysis bullosa (DEB). His group was the first to clone the type VII collagen gene, identify mutations underlying DEB, and perform the first prenatal testing in EB. He and his collaborators developed the first DEB mouse model that has served as a platform for preclinical testing of treatment modalities, including gene, protein and cell based therapies.