Our research Completed projects LENTICOL F (2019) Can gene-modified skin cells provide a useful treatment for RDEB? Contents: Project information Lay summary Grant Title: A prospective phase I study of lentiviral-mediated COL7A1 gene-corrected autologous fibroblast therapy in adults with recessive dystrophic epidermolysis bullosa (LENTICOL-F) Investigator: Professor John McGrath, Professor of Molecular Dermatology and Consultant Dermatologist Co-applicants: Professor Jemima Mellerio, Professor Waseem Qasim, Dr Wei-Li Di, Professor Adrian Thrasher Institutions: St John’s Institute of Dermatology and Institute of Child Health Grant: £499,320 (01/02/2015 – 31/01/2018) Sohana Research Fund now CURE EB Lay Summary Recessive dystrophic epidermolysis bullosa (RDEB) is caused by damage in a gene called COL7A1 that controls the production of a protein – type 7 collagen (C7) in the skin. C7 is an important sticky protein that glues the outer and inner layers of the skin together through hook-like structures called anchoring fibrils. In RDEB, the lack of C7 leads to blisters. Being able to restore C7 in the RDEB skin by gene therapy would lead to fewer blisters and stronger skin. The team at St John’s Institute developed a gene therapy approach to try to restore C7 in RDEB skin. Laboratory research was carried out to make an artificial copy of the COL7A1 gene and to deliver the new gene into skin cells called fibroblasts. The fibroblasts are cells which are normally found in the inner layer of the skin. They can make collagens and other proteins that keep skin healthy. Once the researchers had established that the skin cells could be corrected to make new C7 proteins, they carried out the essential safety checks and work to produce a high-grade gene therapy product that could be used in people with RDEB. After this work was completed, the LENTICOL-F clinical trial (see Figure 1) was set up to test whether this form of gene therapy was safe to use in humans. STUDY PARTICIPANTS AND GENE THERAPY INJECTIONS: Four individuals with RDEB participated in the study and completed the 12 months’ follow up. Each participant enrolled into the study received 3 injections of their own fibroblasts that had been altered to include the new COL7A1 gene. The injections were given into the left upper arm and each area of cell injection measured 1 cm x 1 cm. The cells were prepared at the Institute of Child Health and transported to Guy’s Hospital where the injections took place. The main objective was to see if the cell injections were safe and so participants were carefully followed up for one year. Figure 1: Steps involved in the LENTICOL-F trial. RESULTS: Genetically modified fibroblasts were well tolerated without any adverse effects. No immune reactions were detected against the gene therapy administered. Regarding efficacy, there was a significant ~1.3-to 26-times increase in the C7 protein production in the injected skin compared to non-injected skin in 3 of 4 participants. This effect was still maintained at 12 months in 2 of 4 participants. The presence of the genetically modified COL7A1 gene in the injected skin at Month 12 was recorded in one subject although no new mature anchoring fibrils were detected. CONCLUSION: This is the first human study of an injectable fibroblast gene therapy that was shown to be safe and which can potentially restore the missing C7 protein in the skin of individuals with RDEB. These findings indicate that fibroblast gene therapy may hold promise as a potentially effective therapy for RDEB and provide a justification to conduct larger clinical trials for further evaluation. The results of this study have been published in The Journal of Clinical Investigation Insight: https://insight.jci.org/articles/view/126243 What is important about this research? Dr Su Lwin, Dermatology Registrar at Guy’s and St Thomas’ and Honorary Clinical Research Fellow, Genetic Skin Disease Group, King’s College London, and who was the main researcher on the LENTICOL-F trial said: “This is the very first human study demonstrating that gene-modified patient’s own fibroblasts – commonest skin cells that produce the missing C7 protein– are safe and may hold promise as an effective therapy for individuals with RDEB but bigger trials are needed for further evaluation in the first instance.” Professor John McGrath, the Principal Investigator for the LENTICOL-F trial added “Gene therapy holds great promise for improving the skin of people living with EB. This clinical trial has generated important safety data and provides us with the encouragement to expand our gene therapy work to develop more effective treatments for EB.” Investigator biography John McGrath MD FRCP FMedSci John McGrath holds the Mary Dunhill Chair in Cutaneous Medicine at the St John’s Institute of Dermatology, King’s College London, and is Head of Department for the St John’s Institute of Dermatology and its Genetic Skin Disease Unit, as well as Honorary Consultant Dermatologist to the Guy’s and St Thomas’ NHS Foundation Trust in London. His main interests are in genetics and regenerative medicine and how these impact on dermatology and skin diseases. He is involved in several next generation sequencing initiatives to improve diagnostics for genodermatoses and is also chief investigator for a number of early phase clinical trials of cell and gene therapies for patients with inherited skin diseases.