Professor John McGrath
John McGrath MD FRCP FMedSci is Professor of Molecular Dermatology at King’s College London and Head of the Genetic Skin Disease Unit, as well as Honorary Consultant Dermatologist at St John’s Institute of Dermatology, the Guy’s and St Thomas’ NHS Foundation Trust in London. He leads and collaborates on several National and International projects to develop gene, cell, protein and drug therapies that can lead to better treatments for people living with EB.
Prof McGrath’s research interest lies in discovering what causes inherited skin diseases, how these abnormalities disrupt skin structure and function, and what clinician-scientists can do to develop new clinical and therapeutic benefits for people with genetic skin diseases.
Key objectives are to improve and expand prenatal testing options for families at risk for inherited skin diseases and to advance new therapies for affected individuals, which include cell-based, gene, protein and drug treatments. The McGrath research group has a track record in identifying the molecular basis of inherited skin diseases. Key recent discoveries include the first gene mutations in several forms of epidermolysis bullosa, Kindler syndrome, lipoid proteinosis, and primary cutaneous amyloidosis. The Group also discovered the first inherited disorders of desmosomes.
Translational research involves close liaison with the Robin Eady National Diagnostic Epidermolysis Bullosa Laboratory and clinical services for individuals with epidermolysis bullosa provided by the Guy’s and St Thomas’ NHS Foundation Trust.
The McGrath research Group has pioneered fetal skin biopsy and DNA-based methods for the prenatal diagnosis of inherited skin diseases and performed the first successful preimplantation genetic diagnosis analyses.
Study Lay Summary
Mesenchymal stromal cells (MSC) are multipotent cells capable of maturing into a variety of cell types, but they also have anti-inflammatory properties. Intravenous infusion of MSCs (introducing the cells directly into the person’s blood stream) have been shown to benefit patients who have had heart attacks, renal failure, stroke, diabetes, Crohn’s and Parkinson’s diseases. However, we do not fully understand how this is achieved. The cells do not become incorporated into the recipient’s tissue – in fact they seem to be removed within days, and disappear harmlessly, but they seem to be stimulating anti-inflammatory responses in the recipient that persist for many days or weeks. People with Recessive Dystrophic Epidermolysis Bullosa (RDEB) have a number of complications closely linked to inflammatory reactions; these include anaemia, bone thinning (osteoporosis), poorly healing wounds, itching, loss of appetite and a general failure to thrive. Early results from the EBSTEM study have shown that the infusions appear safe and may have some beneficial effect in children. An important observation is that individuals can respond differently to MSCs, leading researchers to believe that people may have some factors in their inherent biological make-up that makes them good or poor responders. ADSTEM plans to assess the safety of MSCs in adults. This trial will increase understanding of the inflammatory responses in RDEB, help evaluate whether MSCs have the potential to be a useful therapy, and consolidate how this kind of therapy can be given and aid development of future studies in RDEB.
What is important about this research?
“Adults with RDEB often have more scarring and a greater skin cancer risk compared to children and so defining the safety profile of MSCs as a potential therapy for adults is an important objective.”
A prospective phase I study of lentiviral-mediated COL7A1 gene-corrected autologous fibroblast therapy in adults with recessive dystrophic epidermolysis bullosa
Study Lay summary
In Recessive Dystrophic Epidermolysis Bullosa (RDEB) there are inherited mutations (mistakes) in the gene COL7A1 that produces a specific type of protein (collagen VII). The mutations mean that the C7 produced cannot fulfil its normal function of holding the skin layers together to maintain normal skin integrity, so the skin blisters. If normal C7 structure could be restored, this would lead to fewer blisters and stronger skin.
Previously, the research group have shown that they can take the collagen-producing cells (called fibroblasts) from RDEB patients, grow them in the laboratory and introduce a perfect version of the COL7A1 gene using a harmless virus (lentivirus). These treated cells are called “gene-corrected fibroblasts” and can produce perfect C7. This study will recruit adults with RDEB to produce “person-specific” gene-corrected fibroblasts. When sufficient cells have been grown, they will be injected back into the donor’s skin. The study is focusing primarily on safety; however, scientific information on C7 production will also be collected. The results from this work will help in planning further clinical trials. If the gene-corrected cells are safe and show some improvement in the skin structure then the research will progress to other studies – such as comparing gene corrected and uncorrected fibroblasts cells. This technology could be used to correct other cell types such as bone marrow stem cells which could be delivered by intravenous injections and thus could show benefit throughout the body and not just in the local area of skin.
What is important about this research?
“If safety can be established, future trials will compare the genetically corrected cells with uncorrected cells injected into the skin, but the data will also help plan trials of delivering gene therapy to other cells that can be delivered via the bloodstream to help target the whole body. Such work is likely to edge us closer to more effective treatments for RDEB.”
Prof McGrath Publications